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ReviewFebruary 7, 2016

Natural Products as Sources of New Drugs from 1981 to 2014
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David J. Newman^*^†
Gordon M. Cragg^‡

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Journal of Natural Products

Cite this: J. Nat. Prod. 2016, 79, 3, 629–661

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https://doi.org/10.1021/acs.jnatprod.5b01055

Published February 7, 2016

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Abstract

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This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than “S” (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore it is considered that this area of natural product research should be expanded significantly.

Subjects

SPECIAL ISSUE

This article is part of the Special Issue in Honor of John Blunt and Murray Munro special issue.

Introduction

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It is now 18 years since the publication of our first review covering drugs from 1984 to 1995; (1) 12 years since the second, which covered the period from 1981 to 2002; (2) eight years since our third, covering the period 1981 to the middle of 2006; (3) and four years (4) since our last full analysis (covering the period 1981 to 2010), of the sources of new and approved drugs for the treatment of human diseases. In the present review we have also covered the four years from the beginning of 2011 to the end of 2014. In the last four years we have also published intermediate reports on natural products as leads to potential drugs, (5) the sources of antitumor compounds, (6) a general discussion on bioactive macrocycles from Nature, (7) an e-book series on natural products from microbial sources, (8-10) and a very recent book chapter on natural products in medicinal chemistry. (11) All of these articles have emphasized that natural product and/or natural product structures continue to play a highly significant role in the drug discovery and development process.

In Table 1, we have shown the genesis of our category codes and the years that we started with them. This is for the benefit of readers who are not familiar with these definitions and their derivation. The detailed reasoning behind the subgroup definition is given later under results.

Table 1. Codes Used in Analyses

code	brief definition/year
B	Biological macromolecule, 1997
N	Unaltered natural product, 1997
NB	Botanical drug (defined mixture), 2012
ND	Natural product derivative, 1997
S	Synthetic drug, 1997
S*	Synthetic drug (NP pharmacophore), 1997
V	Vaccine, 2003
/NM	Mimic of natural product, 2003

That Nature in one guise or another has continued to influence the design of small molecules is shown by inspection of the information given below, where with the advantage of now 34 years of data from 1981 to 2014 the system has been able to be refined. We have eliminated some duplicated entries that crept into the original data sets and have continued to revise some source designations, as newer information has been obtained from diverse sources. In particular, as behooves authors originally from the National Cancer Institute (NCI), in the specific case of cancer treatments, we have continued to consult the records of the U.S. FDA and have added comments from investigators who have informed us of compounds that may have been approved in other countries and that were not included in our earlier searches. As was done previously, the cancer data will be presented as a stand-alone section from the beginning of formal chemotherapy in the very late 1930s or early 1940s to the present, but information from the last 34 years will be included in the data sets used in the overall discussion.

A trend mentioned in our 2003 review, (2) namely, the development of high-throughput screens based on molecular targets, had led to a demand for the generation of large libraries of compounds; however, the shift away from large combinatorial libraries that was becoming obvious at that time has continued even today, with the emphasis continuing to be on small focused (100–3000 plus) collections that contain much of the “structural aspects” of natural products. As mentioned in our 2012 review, (4) various names have been given to this process, including “diversity oriented syntheses”, (12-16) but we prefer to refer simply to “more natural-product-like”, in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule, (17) or even “natural product mimics” if they happen to be direct competitive inhibitors of the natural substrate (the origin of our subset listed as “?/NM”). It should also be pointed out, yet again, that Lipinski’s fifth rule effectively states that the first four rules do not apply to natural products nor to any molecule that is recognized by an active transport system when considering “druggable chemical entities”. (18-20) An excellent paper by Koehn in 2012 gives a listing in Table 1 in that article of the 26 drugs approved between 1981 and 2011 based on 18 natural product structures that do not obey the “rule of 5” and its strictures. (21) This paper together with one from Sweden by Doak et al. (22) and a very recent contribution by Camp et al. (23) should be part of any discussion on this aspect of natural product drugs.

Commentaries on the “industrial” perspective in regard to drug sources and high-throughput screening were published by the GSK group (24) in 2011, and very recently an intriguing article on what has been called “high throughput screening-dark chemical matter” (HTS-DCM) has opened the discussion on molecules, some of which are based on natural products, that show no activities in in vitro assays but a number of which have very close structural analogues that are active. (25, 26) These papers, the first of which is a perspective on the second much larger paper, should also be read in conjunction with a recent paper showing the natural product compound equivalents (invalid metabolic panaceas (IMPS)) (27) to the pan-assay interference compounds (PAINS) that cause major problems in HTS programs. (28, 29)

Although combinatorial chemistry in one or more of its manifestations has now been present as a discovery source for approximately 80% of the time covered by this review, to date, we still can only find one formal denovo new chemical entity reported in the public domain, with a second possibility discovered in a similar manner, with both approved for drug use. The first was the antitumor compound known as sorafenib (Nexavar, 1) from Bayer, approved by the FDA in 2005 for treatment of renal cell carcinoma, and then in 2007, another approval was given for treatment of hepatocellular carcinoma. It has been approved in more than 100 countries as of the middle of 2014 for these two indications, and in late 2013, the U.S. FDA approved it for treatment of thyroid cancer with further approval for the same indication following in 2014 in the European Union and Japan. As is customary, it is still in multiple clinical trials in both combination and single-agent therapies. The second drug that probably came about from a de novo sourcing is ataluren (Translarna; 2), (30) which was approved in the EU in 2014 and launched in Germany the same year for the treatment of patients with genetic disorders due to a “nonsense” mutation. The mechanism of this small molecule can be seen in a diagrammatic mode at the following URL: http://www.ptcbio.com/en/pipeline/ataluren-translarna/. However, the first anticancer drug constructed by use of fragment screening and model fitting, vemurafenib (3), was approved by the FDA in 2011, and the story behind this and other small-molecule antitumor agents was well described in a review in 2012 by Hoelder et al., which should be consulted for more information on this style of approach to drug discovery. (31)

As mentioned by the present authors and a significant number of other authors in prior reviews on this topic, the developmental capability of combinatorial chemistry as a means for structural optimization, once an active skeleton has been identified, is without par. An expected surge in productivity, however, did not appear to materialize in the years from 2004 to 2014. Thus, the number of new active substances (NASs) from our data set, also known as new chemical entities (NCEs), which we consider to encompass all molecules, including biologics and vaccines, hit a 24-year low of 24 in 2004 (although 7, or 29%, of these were assigned to the “ND” category), leading to a rebound to 52 in 2005, with 25% being “N” or “ND” and 37% being biologics (“B”) or vaccines (“V”). The next four years from 2006 to 2009 averaged 40, with 35–45% being vaccines or biologics, although in these four years, four “botanicals” were approved. In 2010 and 2011, the figures again dropped to 33 and 34, respectively, but then in 2012 to 2014, the figures rebounded to 60, 47, and 65, respectively, but biologics and vaccines were significant proportions of these totals.

These figures are further developed covering the full details by year in Figures 2 and 4 (see the Discussion section below), together with other graphs such as Figure 5, showing total small molecules/year, Figure 6, showing the percentage of natural-product-based compounds and their derivatives. Plus in this review, we have also added the S* series of compounds to these. The use of the S* classification originally arose as a result of doubts expressed by some colleagues working in the chemical synthesis area who questioned the claim that nucleoside analogues synthesized in the laboratory actually evolved from the discoveries by the Bergmann group in the 1950s of the arabinose-containing natural products from marine sponges. (32-34)

The justification for the addition of the “S*” category to natural-product-based compounds and their derivatives in this review is that a large number of the “S*” structures are based on naturally derived nucleosides or very closely related scaffolds, and their relevance to drug discovery will be published in a review in the first half of 2016. Figure 7 then shows the percentage of just the “N*” categories over the 34 years. What is of significant importance in this area is the very recent paper from the Gerwick group demonstrating the isolation of spongosine (4) from a Vibrio harveyi strain isolated from the same sponge species (Tectitethya crypta) as used by Bergmann 60+ years earlier. (35) However, to allow for comparisons with earlier reviews, we have not altered the categories in the analyses. Fortunately, however, research is still being conducted by (bio)synthetic groups on the modification of active natural product skeletons as leads to novel agents. This was exemplified recently by publications in 2014–2015 from the groups of Szychowski et al., (36) Bathula, (37) Thaker, (38) Williams, (39) Miller, (40) and Novaes et al. (41) and an excellent perspective by Nicolaou in 2014. (42)

Against this backdrop, we now present an updated analysis of the role of natural products in the drug discovery and development process, dating from January 1981 through December 2014. As in our earlier analyses, (1-4) we have consulted the Annual Reports of Medicinal Chemistry, in this case from 1984 to 2014, (43-74) and to obtain more comprehensive coverage of the 1981–2014 time frame we have added data from the publication Drug News and Perspective, (75-95) the successor listings in Drugs of Today, (96-101) and searches of the Prous (now Thomson-Reuter’s Integrity) database, as well as by including information from individual investigators. As in the last review, the biologics data prior to 2005 were updated using information culled from disparate sources that culminated in a 2005 review on biopharmaceutical drugs. (102) We have continued our attempts to capture vaccine data for the past few years, but this area of the database is still not as complete as we would hope.

As in previous reviews in this series, we have continued to include relevant references in a condensed form in Tables 3–6 and 9–11. If we had attempted to provide full citations, the numbers of references cited in the present review would become overwhelming. In these tables, “ARMC ##” refers to the volume of Annual Reports in Medicinal Chemistry together with the page on which the structure(s) and commentary can be found. We should point out that due to a change effective in 2015, the ARMC is now known as Medicinal Chemistry Reviews. Similarly, “DNP ##” refers to the volume of Drug News and Perspective and the corresponding page(s), although this journal has now ceased publication as of the 2010 volume. Similarly “DT ##” refers to the relevant volume of Drugs of Today and the corresponding page(s), and an “I ######” is the accession number in the Prous (now Thomson-Reuters, Integrity) database. Finally, in the overall listing of antitumor agents from the middle 1930s to 2014 (Table 9) we have used “Boyd” to refer to a review article (103) on clinical antitumor agents, an earlier book on the same subject, (104) and “M’dale” to refer to Martindale (105) with the relevant page noted.

It must be noted that the “year” header in all tables is formally equivalent to the “year of introduction” of the drug in the first country in which it was approved. We only count a drug once, even if subsequently it is approved in other countries or for other indications. Over the years, we have realized that there are discrepancies between sources as to the actual year, often due to differences in definitions between sources. Some reports will use the year of approval (registration by non-USA FDA equivalent organizations), while others will use the first recorded sales. We have generally taken the earliest year in the absence of further information.

Results

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As in previous reviews, we have, except in a case that will be noted later in this review where a therapy used NCEs (two unapproved agents) in the approved combination, only covered NCEs in the present analysis. As mentioned in earlier reviews, if one reads the U.S. FDA and PhRMA Web sites, the numbers of New Drug Application (NDA) approvals are in the high tens in some of the past few years. The FDA Drugs Database needs to be assessed by anyone using it for drugs previously approved in other countries versus new drugs only approved in the USA to obtain more accurate figures, and there will be differences due to our noting drugs approved the first time anywhere and then not counting the same compound the first time it was approved by the FDA. Using our data (see Figures 2, 4, and 5) the number of NCEs has ranged from the 20’s to just over 50 per year from 1989 to 2011 and in 2013 for approved NCEs (note that Figures 4 and 5 count only small molecules), although in 2012 and 2014 the figures reached 60 and 65, respectively. The reader needs to bear in mind that our vaccine numbers are not complete, so the overall numbers could increase. If one now removes biologicals and vaccines, thus noting only “small molecules” (including peptides such as Byetta), then the figures show that over the same time frame the numbers have ranged from close to 40 for most of the 1989 to 2000 time frame (except for 2002) to close to 20 from 2001 to 2010, with the exception of 2002 and 2004, when the figures climbed above 30. In the last four years (2011 to 2014), the numbers have now climbed from 28 in 2011 to 44 (cf., Figures 2 and 4).

Figure 1. All new approved drugs 1981–2014; n = 1562.

Figure 2. All new approved drugs by source/year.

Figure 3. All small-molecule approved drugs 1981–2014s; n = 1211.

Figure 4. All small-molecule approved drugs by source/year.

Now with 34 years of data to analyze, it was decided to add another graph to the listings, together with one of significant interest to the natural products community. In Figure 6 we have plotted a bar graph from 1981 to 2014 showing the results in numbers/year when the designations used are an “N” or a subdivision (“NB” or “ND”). This time, we have deliberately included the “S*” designation (for the reasons elaborated earlier), which could be considered as “inspired by a natural product structure”. This figure demonstrates that even in 2014 10 of the 44 approved small-molecule drugs are “N”, “NB”, and “ND” with one “S*”, which account for 25% of the 44 approved NCEs that year. If we just use the “N”, “NB”, and “ND” designations over the complete 34 years, then the mean and standard deviation figures in percentages are 33 ± 9, and in Figure 7 we have shown the percentage for “N*” values by year. Readers can determine their own ratios for their “year of interest”, as desired.

As in our earlier reviews, (1-4) the data have been analyzed in terms of numbers and classified according to their origin using the previous major categories and their subdivisions.

Major Categories of Sources

The major categories used are as follows:

“B”: Biological, usually a large (>50 residues) peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host

“N”: Natural product, unmodifed in structure, though might be semi- or totally synthetic

“NB”: Natural product “botanical drug” (in general these have been recently approved)

“ND”: Derived from a natural product and is usually a semisynthetic modification

“S”: Totally synthetic drug, often found by random screening/modification of an existing agent

“S*”: Made by total synthesis, but the pharmacophore is/was from a natural product

“V”: Vaccine

Subcategory

“NM”: Natural product mimic (see rationale and examples below, as they give the reasoning for the extension of the “S” and “S*” categories from 2003 onward)

In the field of anticancer therapy, the advent in 2001 of Gleevec, a protein tyrosine kinase inhibitor, was justly heralded as a breakthrough in the treatment of leukemia. This compound was classified as an “/NM” on the basis of its competitive displacement of the natural substrate, ATP, in which the intracellular concentrations can approach 5 mM. We have continued to classify most PTK inhibitors that are approved as drugs under the “/NM” category for exactly the same reasons as elaborated in the 2003 review, (2) although nowadays, some later kinase inhibitors are not competitive inhibitors of ATP and thus would not be classified this way. The latest discussion on this aspect of PTKs can be read in the 2015 paper by Fabbro et al. (106) (Fabbro can be considered the “developmental father of Gleevec”), which should be read in conjunction with his 2002 paper on PTKs as targets. (107) In addition, the very interesting recent review by Vijayan et al. (108) should be consulted, as it demonstrates, together with the 2015 paper from Fabbro et al., (106) that kinase modulation occurs in a large number of other diseases, and not just in cancer.

Thus, PTK inhibitors have a wide range of possible targets and, in the cases of some specific approved antitumor-directed kinase inhibitors, have a very large number of “targets” in the human kinome. Thus, sunitinib (5) affects a very considerable number of different kinase “families”, whereas lapatinib (6) is restricted to one class, and the as yet unapproved PTKi selumetinib (AZD6244; 7) appears to be quite specific. These effects can be seen in the figures in the 2015 paper by Fabbro et al. (106) and are further elaborated on by Tilgada et al., (109) demonstrating that the targets of PTKi’s are not just in cancer and related diseases. As previously, we have continued to extend the “/SM” category to cover other direct inhibitors/antagonists of the natural substrate/receptor interaction whether obtained by direct experiment or by in silico studies followed by direct assay in the relevant system.

Figure 6. N, NB, ND, and S* categories by year, 1981–2014.

Figure 7. Percentage of N* by year, 1981–2014.

Similarly, a number of new peptidic drug entities, although formally synthetic in nature, are simply produced by chemical synthetic methods rather than by the use of fermentation or extraction. In some cases, an end group might have been changed for ease of recovery. However, a number of compounds produced totally by synthesis are in fact isosteres of the peptidic substrate and are thus “natural product mimics” in the truest sense of the term. We gave some examples of this type of interplay in our 2012 review, in which we mentioned the path to the “sartans”. (4)

Derivation of Oral Renin Inhibitors

Expanding upon this aspect of chemistry and pharmacology, we now will show how the first orally active renin inhibitor was derived starting from pepstatin. In Scheme 1 we show an idealized representation of the angiotensin system pathway, showing the physiological route from renin (an aspartic proteinase) through to the angiotensin-converting enzyme (ACE), to yield the hexapeptide angiotensin II. It was knowledge that this enzyme is a zinc-containing carboxy-peptidase that enabled the Squibb group back in the 1970s to synthesize the pseudodipeptide captopril (8) as the first ACE inhibitor to be approved by the FDA.

However, the “prime target” in the system is inhibition of renin since that is the enzyme that starts the cascade, and, unlike ACE, it does not hydrolyze the “kinin” peptides (bradykinin, etc.). Renin was known to be an aspartic proteinase, and it could be inhibited by the bacterial peptide pepstatin (9). This compound contains the unusual amino acid statine, which contains as a dipeptide mimic a hydroxyethylene isostere, and it was the basis of a long-term project at Merck to synthesize renin inhibitors, and later HIV-protease inhibitors, based on this substituent mimicking the transition state of the aspartic proteinase/substrate pair. (110, 111) Although none of their peptide structures provided a renin inhibitor that was approved as a drug, their work demonstrated the potential for such substitutions to be effective drug leads, albeit from Ciba-Geigy (now Novartis), en route to an orally active renin inhibitor. The first of what were known as type-I inhibitors (112) contained the dipeptide isostere (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid at the P1–P1′ position and also mimicked angiotensinogen from residue P3 to P1′ using the nomenclature from Schetchter and Berger. (113)

The story of the search for orally active renin inhibitors, although formally nonpeptidic but still containing the hydroxyethylene transition state dipeptide isostere, was given in detail by Novartis scientists in two papers, demonstrating that the search involved significant computerized structure–activity relationships using the crystal structure of human renin to optimize the chemistry, before finally leading to the drug candidate, SPP-100, which became the drug aliskiren (10) and gained FDA approval in March 2007 and EMA approval in August 2007. The first paper, in 2000, (114) gave the chemical basis for the initial discoveries of pseudopeptidic agents and the use of structure-based drug design with modifications around the initial type-I inhibitor (CGP 38′560; 11). The second paper, published in 2003, (115) gave the next chapter in the story, the work leading up to aliskiren. Finally, a thorough analysis of the various molecules and routes leading to aliskiren was published by Novartis scientists in 2010, and this should be consulted for the full story. (116)

Figure 8. All anticancer drugs 1981–2014; n = 174.

Figure 9. Small-molecule anticancer drugs 1940s–2014; n = 136.

Figure 10. All anticancer drugs 1940s–2014 by source; n = 246.

Figure 11. All anticancer drugs 1940s–2014 by source/year; n = 246.

Also of interest are some recent publications that under certain conditions could almost be considered as potential for “repurposing” of this drug and perhaps others with the same target. Following a study on the conformation of aliskiren in solution and when bound to its receptor, by Politi et al., in 2011 (117) the data were used to calculate binding of aliskiren to a model of the HIV protease (an aspartic proteinase). This study also demonstrated that the FDA-approved (2013) SGLT-2 inhibitor canagliflozin (12) and the approved HIV protease inhibitor darunavir (13) may have cross-activities in renin inhibition as well as their regular approved pharmacological targets, thus potentially repurposing these compounds. (118)

Biologically Active Peptides

A review covering the preparation of biologically active peptides was published in 2014 and makes interesting reading when the methodologies are compared with those covering the synthesis of pseudopeptides that inhibit aspartic proteinases. (119)

Modifications of Natural Products by Combinatorial Methods

These techniques often produce entirely different compounds that may bear little if any resemblance to the original lead, but are legitimately assignable to the “/NM” category. In addition to the citations given in our previous reviews covering these methodologies, there have been some recent publications that can be consulted in order to demonstrate how “privileged structures from Nature” are demonstrated sources of molecular skeletons around which one may build libraries. (120-123)

Overview of Results

The data that have been analyzed in a variety of ways are presented as a series of bar graphs and pie charts and two major tables in order to establish the overall picture and then are further subdivided into some major therapeutic areas using a tabular format. The time frame covered is the 34 years from January 1, 1981, to December 31, 2014.

•	New Approved Drugs: From all source categories; pie chart (Figure 1)
•	New Approved Drugs: By source/year; bar graph (Figure 2)
•	Sources of All NCEs: Where four or more drugs were approved per medical indication, their sources are shown, and listings of diseases with ≤3 approved drugs (Table 2)
•	Sources of Small-Molecule NCEs: All subdivisions; pie chart (Figure 3)
•	Sources of Small-Molecule NCEs: By source/year; bar graph (Figure 4)
•	Total Small Molecules: By year; point chart (Figure 5)
•	N/NB/ND and S* Categories: By year; bar graph (Figure 6)
•	Percentage of N* Sources: By year; bar graph (Figure 7)
•	Antibacterial Drugs: Generic and trade names, year, reference, and source (Table 3)
•	Antifungal Drugs: Generic and trade names, year, reference, and source (Table 4)
•	Antiviral Drugs: Generic and trade names, year, reference, and source (Table 5)
•	Antiparasitic Drugs: Generic and trade names, year, reference, and source (Table 6)
•	Anti-infective Drugs: All molecules, source, and numbers (Table 7)
•	Anti-infective Drugs: Small molecules, source, and numbers (Table 8)
•	Anticancer Drugs: Generic and trade names, year, reference by source (Table 9; Figure 8 all drugs pie chart; Figure 9, small molecules pie chart)
•	All Anticancer Drugs (very late 1930s–12/2014): Generic and trade names, year, and reference by source (Table 10; Figure 10 pie chart; Figure 11, bar graph)
•	Antidiabetic Drugs: Generic and trade names, year, reference, and source (Table 11)

The extensive data sets shown in the figures and tables referred to above continue to highlight the continuing role that natural products and structures derived from or related to natural products from all sources have played, and continue to play, in the development of the current therapeutic armamentarium of the physician. Inspection of the data shows the continued important role for natural products in spite of the greatly reduced level of natural-products-based drug discovery programs in major pharmaceutical houses.

Inspection of the rate of NCE approvals as shown in Figures 2 and 4–7 demonstrate that even in 2014 the natural products field is still producing, or is involved in, ∼40% of all small molecules in the years 2000–2008, with a drop to ∼20% in 2009, followed by a rebound to 45% in 2010, and then fluctuation between a low of ∼13% in 2013 to between 25% and 30% in the other years of the second decade of the 21st century. The mean and standard deviation for these 15 years are 34 ± 9%, without including any of the natural-product-inspired classifications (“S*”, “S*/NM”, and “S/NM”).

As was shown in the 2012 review, a significant number of all NCEs still fall into the categories of biological (“B”) or vaccines (“V”), with 351 of 1562, or 23% (differs slightly from Figure 1 due to rounding), over the full 34-year period, and it is admitted that not all of the vaccines approved in these 34 years have been identified. We hope that in the last 14 or 15 years a majority have been captured, although some of the more obscure anti-influenza variants may not have been. Thus, the proportion of approved vaccines may well be higher over the longer time frame. Inspection of Figure 2 shows the significant proportion that these two categories hold in the number of approved drugs from 2000, where, in some years, these categories accounted for ca. 50% of all approvals. If the three “N” categories are included, then the proportions of formally nonsynthetics are even higher for these years, although this figure would increase if the “S*” variants are included.

De Novo Combinatorial Drugs

As mentioned earlier, in spite of many years of work by the pharmaceutical industry devoted to high-throughput screening of very significant numbers of combinatorial chemistry products (cf. Macarron’s (20, 24, 25) and Wassermann’s (26) papers on the industrial perspectives), during this time period, only two approved drugs could be found that fall under the de novo combinatorial category, sorafenib (1) and ataluren (2), with vemurafenib (3) potentially falling into this category due to the use of fragment-based methods.

Natural Product Mimics

Overall, of the 1562 NCEs covering all diseases/countries/sources in the years 01/1981–12/2014, and using the “NM” classifications introduced in our 2003 review, (2) the 334 compounds falling into these categories accounted for 21%, or if using just the small molecules where the divisor drops to 1211, the figure becomes 28%. This demonstrates the influence of “other than formal synthetics” on drug discovery and approval (Figures 1 and 3). In the 2012 review, the corresponding figures were ∼20% for all drugs and 25% for small molecules. (4)

Table 2. New Chemical Entities and Medical Indications by Source of Compound 1/1/1981–12/31/2014^a

indication	total	B	N	NB	ND	S	S/NM	S*	S*/NM	V
COPD	8						3		5
analgesic	17		1			11	3	2
anesthetic	5					5
anti-Alzheimer	6	1	1		1		3
anti-Gaucher’s disease	5	3			1				1
anti-Parkinsonian	12				1	1	5	1	4
antiallergic	18		1	1	4	12
antianginal	5					5
antiarrhythmic	17		1			14			2
antiarthritic	22	6	1	1	3	4	6		1
antiasthmatic	14	1			3	2	6		2
antibacterial	140	1	11		71	29			1	27
anticancer	174	33	17	1	38	23	20	13	24	5
anticoagulant	22	5			13			1	3
antidepressant	27					8	17		2
antidiabetic, types 1 and 2	52	23	1		6	4	11	1	6
antiemetic	11					1	2		8
antiepileptic	17				2	11		2	2
antifungal	32	1			3	25	3
antiglaucoma	14				5		5	1	3
antihistamine	14					14
antihyperprolactinemia	4				4
antihypertensive	80				2	28	15	2	33
anti-inflammatory	51	1			13	37
antimigraine	10					2	1		7
antiobesity	6				1	1	4
antiparasitic	16		2		5	5		3		1
antipsoriatic	11	4		1	3		1	1	1
antipsychotic	11					3	6		2
antithrombotic	30	13	1		5	2	6		3
antiulcer	34	1	1		12	20
antiviral	139	14			4	14	5	24	17	61
anxiolytic	10					8	2
benign prostatic hypertrophy	4		1		1	1	1
bronchodilator	8				2				6
calcium metabolism	20				8	9	3
cardiotonic	13				3	2	3		5
chelator	4					4
contraception	9				8		1
cystic fibrosis	4	1				3
diuretic	6					4	2
erythropoiesis	5	5
gastroprokinetic	4					1	2		1
hematopoiesis	7	7
hemophilia	19	19
hemostatic	4	4
hormone	22	12			10
hormone replacement therapy	8				8
hyperphosphatemia	5					5
hypnotic	12					12
hypocholesterolemic	13		4		1	2	1		5
hypolipidemic	8		1			7
immunomodulator	4	2	1		1
immunostimulant	12	6	3		2	1
immunosuppressant	14	6	5		3
irritable bowel syndrome	5				1	1			3
macular degeneration	6	4			1	1
male sexual dysfunction	5								5
multiple sclerosis	10	4			2	2		1	1
muscle relaxant	10				4	2	1	3
neuroleptic	9					1	6		2
nootropic	8				3	5
osteoporosis	6	3			2	1
platelet aggregation inhibitor	4				3		1
respiratory distress syndrome	7	4	1			1	1
urinary incontinence	6					2	3		1
vasodilation	5				3	2
vulnerary	8	5			2	1
grand total	1328	189	54	4	268	359	149	55	156	94

Diseases where ≤3 drugs approved 1981–2014: 234 drugs fall into this category and are subdivided as follows: B, 81; N, 15; ND, 46; S, 47, S/NM. 15; S*, 4; S*/NM, 18. The diseases covered the following; 5α-reductase inhibitor, ADHD, CAPS, CHF, CNS stimulant, Castleman’s disease, Crohn’s disease, Cushing’s syndrome, Fabry’s disease, Hunter syndrome, inborn errors of bile synthesis, inflammatory bowel disease, Japanese encephalitis, Lambert-Eaton myasthenic syndrome, Lyme disease, acute MI, MMRC, Morquio A syndrome, PAH, PCP/toxoplasmosis, PNH, Pompe’s disease, Turner syndrome, abortifacient, acromelagy, alcohol deterrent, allergic rhinitis, anabolic metabolism, analeptic, anemia, antisickle cell anemia, antismoking, antiacne, antiathersclerotic, anticonvulsant, antidiarrheal, antidote, antiemphysemic, antihyperuricemia, antihypotensive, antinarcolepsy, antinarcotic, antinauseant, antiperistaltic, antiprogestogenic, antirheumatic, antisecretory, antisepsis, antiseptic, antispasmodic, antispastic, antitussive, antityrosinaemia, antixerostomia, atrial fibrillation, benzodiazepine antagonist, β-lactamase inhibitor, blepharospasm, bone disorders, bone morphogenesis, bowel evacuant, cancer adjuvant, cardioprotective, cardiovascular disease, cartilage disorders, cervical dystonia, choleretic, chronic idiopathic constipation, cognition enhancer, congestive heart failure, constipation, coronary artery disease, cystinosis, cytoprotective, diabetic foot ulcers, diabetic neuropathies, digoxin toxicity, dispareunia, dry eye syndrome, dyslipidemia, dysuria, endometriosis, enzyme, expectorant, eye disorders, fertility inducer, free-running circadian disorder, gastroprotectant, genital warts, hematological, hemorrhage, hepatoprotectant, hereditary angioedema, homocystinuria, hyperammonemia, hypercholesterolemia (and familial), hyperparathyroidism, hyperphenylalaninemia, hypertriglyceridemia, hyperuricemia, hypoammonuric, hypocalciuric, hypogonadism, hyponatremia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, immediate allergy, infertility (female), inflammatory bowel disease, insecticide, insomnia, joint lubricant, lipodystrophy (and in HIV), lipoprotein disorders, lipoprotein lipase deficiency, lupus erythematosus, mucolytic, mucopolysaccharidosis, mucositis, myleodysplasia, narcolepsy, nasal decongestant, neuropathic pain, neuroprotective, neutropenia, ocular inflammation, opiate detoxification, opiod-induced constipation, osteoarthritis, overactive bladder, ovulation, pancreatic disorders, pancreatitis, pertussis, photosensitizer, phytotoxicity in adults, pituitary disorders, porphyria, premature birth, premature ejaculation, progestogen, psychostimulant, pulmonary arterial hypertension, purpura fulminans, rattlesnake antivenom, reproduction, restenosis, schizophrenia, sclerosant, secondary hyperthryoidism, sedative, short bowel syndrome, skin photodamage, smoking cessation, strabismus, subarachnoid hemorrhage, thrombocytopenia, treatment of GH deficiency, ulcerative colitis, urea cycle disorders, uremic pruritis, urolithiasis, vaccinia complications, varicella (chicken pox), vasoprotective, venous thromboembolism.

Table 3. Antibacterial Drugs from 1/1/1981 to 12/31/2014 Organized Alphabetically by Generic Name within Source

generic name	trade name	year introduced	volume	page	source
raxibacumab	ABthrax	2012	I 336061		B
carumonam	Amasulin	1988	ARMC 24	298	N
daptomycin	Cubicin	2003	ARMC 39	347	N
fidaxomicin	Dificid	2011	DT 48(1)	40	N
fosfomycin trometamol	Monuril	1988	I 112334		N
isepamicin	Isepacin	1988	ARMC 24	305	N
micronomicin sulfate	Sagamicin	1982	P091082		N
miokamycin	Miocamycin	1985	ARMC 21	329	N
mupirocin	Bactroban	1985	ARMC 21	330	N
netilimicin sulfate	Netromicine	1981	I 070366		N
RV-11	Zalig	1989	ARMC 25	318	N
teicoplanin	Targocid	1988	ARMC 24	311	N
apalcillin sodium	Lumota	1982	I 091130		ND
arbekacin	Habekacin	1990	ARMC 26	298	ND
aspoxicillin	Doyle	1987	ARMC 23	328	ND
astromycin sulfate	Fortimicin	1985	ARMC 21	324	ND
azithromycin	Sunamed	1988	ARMC 24	298	ND
aztreonam	Azactam	1984	ARMC 20	315	ND
biapenem	Omegacin	2002	ARMC 38	351	ND
cefbuperazone sodium	Tomiporan	1985	ARMC 21	325	ND
cefcapene pivoxil	Flomox	1997	ARMC 33	330	ND
cefdinir	Cefzon	1991	ARMC 27	323	ND
cefditoren pivoxil	Meiact	1994	ARMC 30	297	ND
cefepime	Maxipime	1993	ARMC 29	334	ND
cefetamet pivoxil HCl	Globocef	1992	ARMC 28	327	ND
cefixime	Cefspan	1987	ARMC 23	329	ND
cefmenoxime HCl	Tacef	1983	ARMC 19	316	ND
cefminox sodium	Meicelin	1987	ARMC 23	330	ND
cefodizime sodium	Neucef	1990	ARMC 26	300	ND
cefonicid sodium	Monocid	1984	ARMC 20	316	ND
cefoperazone sodium	Cefobis	1981	I 127130		ND
ceforanide	Precef	1984	ARMC 20	317	ND
cefoselis	Wincef	1998	ARMC 34	319	ND
cefotetan disodium	Yamatetan	1984	ARMC 20	317	ND
cefotiam HCl	Pansporin	1981	I 091106		ND
cefozopran HCl	Firstcin	1995	ARMC 31	339	ND
cefpimizole	Ajicef	1987	ARMC 23	330	ND
cefpiramide sodium	Sepatren	1985	ARMC 21	325	ND
cefpirome sulfate	Cefrom	1992	ARMC 28	328	ND
cefpodoxime proxetil	Banan	1989	ARMC 25	310	ND
cefprozil	Cefzil	1992	ARMC 28	328	ND
cefsoludin sodium	Takesulin	1981	I 091108		ND
ceftaroline fosamil acetate	Teflaro	2011	DT 48(1)	40	ND
ceftazidime	Fortam	1983	ARMC 19	316	ND
cefteram pivoxil	Tomiron	1987	ARMC 23	330	ND
Ceftibuten	Seftem	1992	ARMC 28	329	ND
ceftizoxime sodium	Epocelin	1982	I 070260		ND
ceftobiprole medocaril	Zeftera	2008	ARMC 44	589	ND
ceftriaxone sodium	Rocephin	1982	I 091136		ND
cefuroxime axetil	Zinnat	1987	ARMC 23	331	ND
cefuzonam sodium	Cosmosin	1987	ARMC 23	331	ND
cetolozane/tazobactam	Zerbaxa	2014	DT 51(1)	47	ND
clarithromycin	Klaricid	1990	ARMC 26	302	ND
dalbavancin	Dalavance	2014	DT 51(!)	47	ND
dalfopristin	Synercid	1999	ARMC 35	338	ND
dirithromycin	Nortron	1993	ARMC 29	336	ND
doripenem	Finibax	2005	DNP 19	42	ND
ertapenem sodium	Invanz	2002	ARMC 38	353	ND
erythromycin acistrate	Erasis	1988	ARMC 24	301	ND
flomoxef sodium	Flumarin	1988	ARMC 24	302	ND
flurithromycin ethylsuccinate	Ritro	1997	ARMC 33	333	ND
fropenam	Farom	1997	ARMC 33	334	ND
imipenem/cilastatin	Zienam	1985	ARMC 21	328	ND
lenampicillin HCI	Varacillin	1987	ARMC 23	336	ND
loracarbef	Lorabid	1992	ARMC 28	333	ND
meropenem	Merrem	1994	ARMC 30	303	ND
moxalactam disodium	Shiomarin	1982	I 070301		ND
oritavancin	Orbactiv	2014	DT 51(1)	47	ND
panipenem/betamipron	Carbenin	1994	ARMC 30	305	ND
quinupristin	Synercid	1999	ARMC 35	338	ND
retapamulin	Altabax	2007	ARMC 43	486	ND
rifabutin	Mycobutin	1992	ARMC 28	335	ND
rifamixin	Normix	1987	ARMC 23	341	ND
rifapentine	Rifampin	1988	ARMC 24	310	ND
rifaximin	Rifacol	1985	ARMC 21	332	ND
rokitamycin	Ricamycin	1986	ARMC 22	325	ND
roxithromycin	Rulid	1987	ARMC 23	342	ND
sultamycillin tosylate	Unasyn	1987	ARMC 23	343	ND
tazobactam sodium	Tazocillin	1992	ARMC 28	336	ND
telavancin HCl	Vibativ	2009	DNP 23	15	ND
telithromycin	Ketek	2001	DNP 15	35	ND
temocillin disodium	Temopen	1984	ARMC 20	323	ND
tigecycline	Tygacil	2005	DNP 19	42	ND
balafloxacin	Q-Roxin	2002	ARMC 38	351	S
bedaquiline	Sirturo	2012	1 386239		S
besifloxacin	Besivance	2009	DNP 23	20	S
ciprofloxacin	Ciprobay	1986	ARMC 22	318	S
enoxacin	Flumark	1986	ARMC 22	320	S
finafloxacin hydrochloride	Xtoro	2014	DT 51(1)	48	S
fleroxacin	Quinodis	1992	ARMC 28	331	S
garenoxacin	Geninax	2007	ARMC 43	471	S
gatilfloxacin	Tequin	1999	ARMC 35	340	S
gemifloxacin mesilate	Factive	2003	ARMC 40	458	S
grepafloxacin	Vaxor	1997	DNP 11	23	S
levofloxacin	Floxacin	1993	ARMC 29	340	S
linezolid	Zyvox	2000	DNP 14	21	S
lomefloxacin	Uniquin	1989	ARMC 25	315	S
moxifloxacin HCl	Avelox	1999	ARMC 35	343	S
nadifloxacin	Acuatim	1993	ARMC 29	340	S
nemonoxacin	Taigexyn	2014	DT 51(1)	48	S
norfloxacin	Noroxin	1983	ARMC 19	322	S
ofloxacin	Tarivid	1985	ARMC 21	331	S
pazufloxacin	Pasil	2002	ARMC 38	364	S
pefloxacin mesylate	Perflacine	1985	ARMC 21	331	S
prulifloxacin	Sword	2002	ARMC 38	366	S
rufloxacin hydrochloride	Qari	1992	ARMC 28	335	S
sitafloxacin hydrate	Gracevit	2008	DNP 22	15	S
sparfloxacin	Spara	1993	ARMC 29	345	S
taurolidine	Taurolin	1988	I 107771		S
tedizolid phosphate sodium	Sivextro	2014	DT 51(1)	47	S
temafloxacin hydrochloride	Temac	1991	ARMC 27	334	S
tosufloxacin	Ozex	1990	ARMC 26	310	S
trovafloxacin mesylate	Trovan	1998	ARMC 34	332	S
brodimoprin	Hyprim	1993	ARMC 29	333	S*/NM
	Bexsero	2013	DT 50(1)	69	V
	Prevenar 13	2009	DNP 23	17	V
	Quattrovac	2012	I 770186		V
	Synflorix	2009	DNP 23	17	V
	Typbar	2013	DT 50(1)	68	V
ACWY meningoccal PS vaccine	Mencevax	1981	I 420128		V
BK-4SP	Tetrabik	2012	I 697562		V
botulism antitoxin	Bat	2013	DT 50(1)	77	V
DTPw-HepB-Hib	Quinvaxem	2006	DNP 20	26	V
DTP vaccines	Daptacel	2002	I 319668		V
H. influenzae b vaccine	Hibtitek	1989	DNP 03	24	V
H. influenzae b vaccine	Prohibit	1989	DNP 03	24	V
hexavalent vaccine	Hexavac	2000	DNP 14	22	V
hexavalent vaccine	Infantrix HeXa	2000	DNP 14	22	V
Hib-MenCY-TT	Menhibrix	2012	I 421742		V
MCV-4	Menactra	2005	DNP 19	43	V
MenACWY-CRM	Menveo	2010	I 341212		V
MenACWY-TT	Nimenrix	2012	I 421745		V
meningitis b vaccine	MeNZB	2004	DNP 18	29	V
meningococcal vaccine	Menigetec	1999	DNP 14	22	V
meningococcal vaccine	NeisVac-C	2000	DNP 14	22	V
meningococcal vaccine	Menjugate	2000	DNP 14	22	V
MnB rLP2086	Trumenba	2014	DT 51(1)	51	V
oral cholera vaccine	Orochol	1994	DNP 08	30	V
pneumococcal vaccine	Prevnar	2000	DNP 14	22	V
PsA-TT	MenAfriVac	2010	I 437718		V
Vi polysaccharide typhoid vaccine	Typherix	1998	DNP 12	35	V

Table 4. Antifungal Drugs from 1/1/1981 to 12/31/2010 Organized Alphabetically by Generic Name within Source

generic name	trade name	year introduced	volume	page	source
interferon gamma-n1	OGamma100	1996	DNP 10	13	B
anidulafungin	Eraxis	2006	DNP 20	24	ND
caspofungin acetate	Cancidas	2001	DNP 15	36	ND
micafungin sodium	Fungard	2002	ARMC 38	360	ND
amorolfine hydrochloride	Loceryl	1991	ARMC 27	322	S
butoconazole	Femstat	1986	ARMC 22	318	S
ciclopirox olamine	Loprox	1982	I 070449		S
cloconazole HCI	Pilzcin	1986	ARMC 22	318	S
eberconazole	Ebernet	2005	DNP 19	42	S
efinaconazole	Jublia	2013	DT 50(1)	66	S
fenticonazole nitrate	Lomexin	1987	ARMC 23	334	S
fluconazole	Diflucan	1988	ARMC 24	303	S
flutrimazole	Micetal	1995	ARMC 31	343	S
fosfluconazole	Prodif	2003	DNP 17	49	S
itraconazole	Sporanox	1988	ARMC 24	305	S
ketoconazole	Nizoral	1981	I 116505		S
lanoconazole	Astat	1994	ARMC 30	302	S
luliconazole	Lulicon	2005	DNP 19	42	S
naftifine HCI	Exoderil	1984	ARMC 20	321	S
neticonazole HCI	Atolant	1993	ARMC 29	341	S
oxiconazole nitrate	Oceral	1983	ARMC 19	322	S
posaconazole	Noxafil	2005	DNP 19	42	S
sertaconazole nitrate	Dermofix	1992	ARMC 28	336	S
sitafloxacin hydrate	Gracevit	2008	DNP 22	15	S
sulconazole nitrate	Exelderm	1985	ARMC 21	332	S
tavaborole	Kerydin	2014	DT 51(1)	51	S
terconazole	GynoTerazol	1983	ARMC 19	324	S
tioconazole	Trosyl	1983	ARMC 19	324	S
voriconazole	Vfend	2002	ARMC 38	370	S
butenafine hydrochloride	Mentax	1992	ARMC 28	327	S/NM
liranaftate	Zefnart	2000	DNP 14	21	S/NM
terbinafine hydrochloride	Lamisil	1991	ARMC 27	334	S/NM

Table 5. Antiviral Drugs from 1/1/1981 to 12/31/2014 Organized Alphabetically by Generic Name within Source

generic name	trade name	year introduced	volume	page	source
	Oralgen	2007	I 415378		B
IGIV-HB	Niuliva	2009	DNP 23	16	B
immunoglobulin intravenous	Gammagard Liquid	2005	I 231564		B
interferon alfa	Alfaferone	1987	I 215443		B
interferon alfa-2b	Viraferon	1985	I 165805		B
interferon alfacon-1	Infergen	1997	ARMC 33	336	B
interferon alfa-n1	Wellferon	1986	I 125561		B
interferon alfa-n3	Alferon N	1990	DNP 04	104	B
interferon beta	Frone	1985	I115091		B
palivizumab	Synagis	1998	DNP 12	33	B
peginterferon alfa-2a	Pegasys	2001	DNP 15	34	B
peginterferon alfa-2b	Pegintron	2000	DNP 14	18	B
resp syncytial virus IG	RespiGam	1996	DNP 10	11	B
thymalfasin	Zadaxin	1996	DNP 10	11	B
enfuvirtide	Fuzeon	2003	ARMC 39	350	ND
laninamivir octanoate	Inavir	2010	I 340894		ND
oseltamivir	Tamiflu	1999	ARMC 35	346	ND
zanamivir	Relenza	1999	ARMC 35	352	ND
daclatasvir dihydrochloride	Daklinza	2014	DT 51(1)	48	S
dasabuvir	Exviera	2014	DT 51(1)	50	S
delavirdine mesylate	Rescriptor	1997	ARMC 33	331	S
dolutegravir	Tivicay	2013	DT 50(1)	63	S
efavirenz	Sustiva	1998	ARMC 34	321	S
elvitegravir	Viteka	2013	DT 50(1)	63	S
foscarnet sodium	Foscavir	1989	ARMC 25	313	S
imiquimod	Aldara	1997	ARMC 33	335	S
maraviroc	Celsentri	2007	ARMC 43	478	S
nevirapine	Viramune	1996	ARMC 32	313	S
propagermanium	Serosion	1994	ARMC 30	308	S
raltegravir potassium	Isentress	2007	ARMC 43	484	S
rilpivirine hydrochloride	Edurant	2011	DT 48(1)	41	S
rimantadine HCI	Roflual	1987	ARMC 23	342	S
asunaprevir	Sunvepra	2014	DT 51(1)	48	S/NM
cobicistat	Tybost	2013	DT 50(1)	63	S/NM
darunavir	Prezista	2006	DNP 20	25	S/NM
ledipasvir	Harvoni	2014	DT 51(1)	48	S/NM
peramivir	PeramiFlu	2010	I 273549		S/NM
abacavir sulfate	Ziagen	1999	ARMC 35	333	S*
acyclovir	Zovirax	1981	I 091119		S*
adefovir dipivoxil	Hepsera	2002	ARMC 38	348	S*
cidofovir	Vistide	1996	ARMC 32	306	S*
clevudine	Levovir	2007	ARMC 43	466	S*
didanosine	Videx	1991	ARMC 27	326	S*
emtricitabine	Emtriva	2003	ARMC 39	350	S*
entecavir	Baraclude	2005	DNP 19	39	S*
epervudine	Hevizos	1988	I 157373		S*
etravirine	Intelence	2008	DNP 22	15	S*
famciclovir	Famvir	1994	ARMC 30	300	S*
ganciclovir	Cymevene	1988	ARMC 24	303	S*
inosine pranobex	Imunovir	1981	I 277341		S*
lamivudine	Epivir	1995	ARMC 31	345	S*
penciclovir	Vectavir	1996	ARMC 32	314	S*
sofosbuvir	Solvadi	2013	DT 50(1)	64	S*
sorivudine	Usevir	1993	ARMC 29	345	S*
stavudine	Zerit	1994	ARMC 30	311	S*
telbividine	Sebivo	2006	DNP 20	22	S*
tenofovir disoproxil fumarate	Viread	2001	DNP 15	37	S*
valaciclovir HCl	Valtrex	1995	ARMC 31	352	S*
valganciclovir	Valcyte	2001	DNP 15	36	S*
zalcitabine	Hivid	1992	ARMC 28	338	S*
zidovudine	Retrovir	1987	ARMC 23	345	S*
amprenavir	Agenerase	1999	ARMC 35	334	S*/NM
atazanavir	Reyataz	2003	ARMC 39	342	S*/NM
boceprevir	Victrelis	2011	DT 48(1)	41	S*/NM
favipiravir	Avigan	2014	DT 51(1)	50	S*/NM
fomivirsen sodium	Vitravene	1998	ARMC 34	323	S*/NM
fosamprenevir	Lexiva	2003	ARMC 39	353	S*/NM
indinavir sulfate	Crixivan	1996	ARMC 32	310	S*/NM
lopinavir	Kaletra	2000	ARMC 36	310	S*/NM
neflinavir mesylate	Viracept	1997	ARMC 33	340	S*/NM
ombitasvir	Viekira Pak	2014	DT 51(1)	50	S*/NM
paritaprevir	Viekira Pak	2014	DT 51(1)	50	S*/NM
ritonavir	Norvir	1996	ARMC 32	317	S*/NM
saquinavir mesylate	Invirase	1995	ARMC 31	349	S*/NM
simeprevir	Sovirad	2013	DT 50(1)	63	S*/NM
telaprevir	Incivek	2011	DT 48(1)	41	S*/NM
tipranavir	Aptivus	2005	DNP 19	42	S*/NM
vaniprevir	Vanihep	2014	DT 51(1)	49	S*/NM
	ACAM-2000	2007	I 328985		V
	Bilive	2005	DNP 19	43	V
	Celtura	2009	DNP 23	17	V
	Celvapan	2009	DNP 23	17	V
	Daronix	2007	I 427024		V
	Fluval P	2009	DNP 23	17	V
	Fluzone Quadrivalent	2013	DT 50(1)	68	V
	Focetria	2009	DNP 23	17	V
	Grippol Neo	2009	DNP 23	16	V
	Hexyon	2013	DT 50(1)	69	V
	Imvanex	2013	DT 50(1)	69	V
	Optaflu	2007	I 410266		V
	Pandremix	2009	DNP 23	17	V
	Panenza	2009	DNP 23	17	V
	Panflu	2008	DNP 22	16	V
	Vaxiflu-S	2010	I 698015		V
	VariZIG	2005	I 230590		V
	Vepacel	2012	I 768351		V
9vHPV	Gardasil 9	2014	DT 51(1)	52	V
HPV vaccine	Gardasil	2006	DNP 20	26	V
anti-Hep B immunoglobulin	HepaGam B	2006	DNP 20	27	V
antirabies vaccine	Rabirix	2006	DNP 20	27	V
attenuated chicken pox vaccine	Merieux Varicella	1993	DNP 07	31	V
BBIL/JEV	Jenvac	2013	DT 50(1)	68	V
chimerivax-JE	Imojev	2012	I 292954		V
CSL-401	Panvax	2008	DNP 22	16	V
FLU-Q-QIV	Fluarix Quadrivalent	2012	DT 50(1)	68	V
GSK-1562902A	Prepandrix	2008	DNP 22	16	V
GSK-2282512A	Fluarix Quadrivalent	2012	I 709665		V
H5N1 avian flu vaccine		2007	I 440743		V
hepatitis a vaccine	Aimmugen	1995	DNP 09	23	V
hepatitis a vaccine	Havrix	1992	DNP 06	99	V
hepatitis a vaccine	Vaqta	1996	DNP 10	11	V
hepatitis b vaccine	Biken-HB	1993	DNP 07	31	V
hepatitis b vaccine	Bio-Hep B	2000	DNP 14	22	V
hepatitis b vaccine	Engerix B	1987	I 137797		V
hepatitis b vaccine	Fendrix	2005	DNP 19	43	V
hepatitis b vaccine	Hepacure	2000	DNP 14	22	V
hepatitis b vaccine	Meinyu	1997	DNP 11	24	V
hepatitis a and b vaccine	Ambirix	2003	I 334416		V
HN-VAC	HNVAC	2010	I 684608		V
inact hepatitis a vaccine	Avaxim	1996	DNP 10	12	V
influ A (H1N1) monovalent		2010	I 678265		V
influenza vaccine	Invivac	2004	I 391186		V
influenza vaccine	Optaflu	2008	DNP 22	16	V
influenza virus (live)	FluMist	2003	ARMC 39	353	V
influenza virus vaccine	Afluria	2007	I 449226		V
KD-295		2014	DT 51(1)	52	V
measles/rubella vaccine		2011	DT 48(1)	44	V
Medi-3250	FluMist Quadrivalent	2012	I 669909		V
MR vaccine	Mearubik	2005	DNP 19	44	V
rec hepatitis B vaccine	Supervax	2006	DNP 20	27	V
rotavirus vaccine	Rotarix	2005	DNP 18	29	V
rotavirus vaccine	Rota-Shield	1998	DNP 12	35	V
rotavirus vaccine	Rotateq	2006	DNP 20	26	V
rubella vaccine	Ervevax	1985	I 115078		V
varicella virus vaccine	Varivax	1995	DNP 09	25	V
VCIV	PreFluCel	2010	I 444826		V
zoster vaccine live	Zostavax	2006	DNP 20	26	V

Table 6. Antiparasitic Drugs from 1/1/1981 to 12/31/2014 Organized Alphabetically by Generic Name within Source

generic name	trade name	year introduced	volume	page	source
artemisinin	Artemisin	1987	ARMC 23	327	N
ivermectin	Mectizan	1987	ARMC 23	336	N
arteether	Artemotil	2000	DNP 14	22	ND
artemether	Artemetheri	1987	I 90712		ND
artesunate	Arinate	1987	I 91299		ND
eflornithine HCl	Ornidyl	1990	DNP 04	104	ND
mefloquine HCI	Fansimef	1985	ARMC 21	329	ND
albendazole	Eskazole	1982	I 129625		S
delamanid	Deltyba	2014	DF 51(1)	48	S
halofantrine	Halfan	1988	ARMC 24	304	S
lumefantrine	?	1987	I 269095		S
quinfamide	Amenox	1984	ARMC 20	322	S
atovaquone	Mepron	1992	ARMC 28	326	S*
bulaquine/chloroquine	Aablaquin	2000	DNP 14	22	S*
trichomonas vaccine	Gynatren	1986	I 125543		V

Table 7. All Anti-infective (Antibacterial, Fungal, Parasitic, and Viral) Drugs (n = 326)

indication	total	B	N	ND	S	S/NM	S*	S*/NM	V
antibacterial	141	1	11	71	29			1	28
antifungal	32	1		3	25	3
antiparasitic	15		2	5	5		2		1
antiviral	138	14		4	14	5	24	17	60
total	326	16	13	83	73	8	26	18	89
percentage	100	4.9	4.0	25.5	22.4	2.4	8.0	5.5	27.3

Table 8. Small-Molecule Anti-infective (Antibacterial, Fungal, Parasitic, and Viral) Drugs (n = 221)

indication	total	N	ND	S	S/NM	S*	S*/NM
antibacterial	112	11	71	29			1
antifungal	31		3	25	3
antiparasitic	14	2	5	5		2
antiviral	64		4	14	5	24	17
total	221	13	83	73	8	26	18
percentage	100	5.9	37.6	33.0	3.6	11.8	8.1

Table 9. Anticancer Drugs from 1/1/1981 to 12/31/2014 Organized Alphabetically by Generic Name within Source

generic name	trade name	year introduced	volume	page	source
	Rexin-G	2007	I 346431		B
131I-chTNT		2007	I 393351		B
alemtuzumab	Campath	2001	DNP 15	38	B
bevacizumab	Avastin	2004	ARMC 40	450	B
blinatumomab	Blincyto	2014	DT 51(1)	55	B
catumaxomab	Removab	2009	DNP 23	18	B
celmoleukin	Celeuk	1992	DNP 06	102	B
cetuximab	Erbitux	2003	ARMC 39	346	B
denileukin diftitox	Ontak	1999	ARMC 35	338	B
H-101		2005	DNP 19	46	B
ibritumomab	Zevalin	2002	ARMC 38	359	B
interferon alfa2a	Roferon-A	1986	I 204503		B
interferon, gamma-1a	Biogamma	1992	ARMC 28	332	B
interleukin-2	Proleukin	1989	ARMC 25	314	B
ipilimumab	Yervoy	2011	DT 48(1)	45	B
mobenakin	Octin	1999	ARMC 35	345	B
mogamulizumab	Poteligeo	2012	I 433141		B
nimotuzumab	BIOMAb EFGR	2006	DNP 20	29	B
nivolumab	Optivo	2014	DT 51(1)	56	B
obinutuzumab	Gazyva	2013	DT 50(1)	70	B
ofatumumab	Arzerra	2009	DNP 23	18	B
panitumumab	Vectibix	2006	DNP 20	28	B
pegaspargase	Oncaspar	1994	ARMC 30	306	B
pembrolizumab	Keytruda	2014	DT 51(1)	56	B
pertuzumab	Omnitarg	2012	I 300439		B
racotumomab	Vaxira	2013	DT 50(1)	72	B
ramucirumab	Cyramza	2014	DT 51(1)	55	B
rituximab	Rituxan	1997	DNP 11	25	B
sipuleucel-T	Provenge	2010	I 259673		B
tasonermin	Beromun	1999	ARMC 35	349	B
teceleukin	Imumace	1992	DNP 06	102	B
tositumomab	Bexxar	2003	ARMC 39	364	B
trastuzumab	Herceptin	1998	DNP 12	35	B
aclarubicin	Aclacin	1981	P090013		N
aminolevulinic acid HCl	Levulan	2000	DNP 14	20	N
angiotensin II	Delivert	1994	ARMC 30	296	N
arglabin	?	1999	ARMC 35	335	N
homoharringtonine	Ceflatonin	2012	I 090682		N
ingenol mebutate	Picato	2012	I 328987		N
masoprocol	Actinex	1992	ARMC 28	333	N
paclitaxel	Taxol	1993	ARMC 29	342	N
paclitaxel nanoparticles	Abraxane	2005	DNP 19	45	N
paclitaxel nanoparticles	Nanoxel	2007	I 422122		N
paclitaxel nanoparticles	Genexol-PM	2007	I 811264		N
paclitaxel nanoparticles	PICN	2014	DT 51(1)	58	N
pentostatin	Nipent	1992	ARMC 28	334	N
peplomycin	Pepleo	1981	I090889		N
romidepsin	Istodax	2010	DNP 23	18	N
trabectedin	Yondelis	2007	ARMC 43	492	N
solamargines	Curaderm	1989	DNP 03	25	NB
abiratenone acetate	Zytiga	2011	DT 48(1)	44	ND
alitretinoin	Panretin	1999	ARMC 35	333	ND
aminolevulinic-CO₂CH₃	Metvix	2001	DNP 15	34	ND
amrubicin HCl	Calsed	2002	ARMC 38	349	ND
belotecan hydrochloride	Camtobell	2004	ARMC 40	449	ND
bf-200 ala	Ameluz	2012	I 431098		ND
brentuximab vedotin	Adcetris	2011	DT 48(1)	45	ND
cabazitaxel	Jevtana	2010	I 287186		ND
carfilzomib	Kyprolis	2012	I 413092		ND
cladribine	Leustatin	1993	ARMC 29	335	ND
cytarabine ocfosfate	Starsaid	1993	ARMC 29	335	ND
docetaxel	Taxotere	1995	ARMC 31	341	ND
elliptinium acetate	Celiptium	1983	I091123		ND
epirubicin HCI	Farmorubicin	1984	ARMC 20	318	ND
eribulin	Halaven	2010	I 287199		ND
etoposide phosphate	Etopophos	1996	DNP 10	13	ND
exemestane	Aromasin	1999	DNP 13	46	ND
formestane	Lentaron	1993	ARMC 29	337	ND
fulvestrant	Faslodex	2002	ARMC 38	357	ND
gemtuzumab ozogamicin	Mylotarg	2000	DNP 14	23	ND
hexyl aminolevulinate	Hexvix	2004	I 300211		ND
idarubicin hydrochloride	Zavedos	1990	ARMC 26	303	ND
irinotecan hydrochloride	Campto	1994	ARMC 30	301	ND
ixabepilone	Ixempra	2007	ARMC 43	473	ND
mifamurtide	Junovan	2010	DNP 23	18	ND
miltefosine	Miltex	1993	ARMC 29	340	ND
pirarubicin	Pinorubicin	1988	ARMC 24	309	ND
pralatrexate	Folotyn	2009	DNP 23	18	ND
talaporfin sodium	Laserphyrin	2004	ARMC 40	469	ND
temsirolimus	Toricel	2007	ARMC 43	490	ND
topotecan HCl	Hycamptin	1996	ARMC 32	320	ND
trastuzumab emtansine	Kadcyla	2013	DT 50(1)	69	ND
triptorelin	Decapeptyl	1986	I 090485		ND
valrubicin	Valstar	1999	ARMC 35	350	ND
vapreotide acetate	Docrised	2004	I 135014		ND
vinflunine	Javlor	2010	I 219585		ND
vinorelbine	Navelbine	1989	ARMC 25	320	ND
zinostatin stimalamer	Smancs	1994	ARMC 30	313	ND
aminoglutethimide	Cytadren	1981	I 070408		S
amsacrine	Amsakrin	1987	ARMC 23	327	S
arsenic trioxide	Trisenox	2000	DNP 14	23	S
bisantrene hydrochloride	Zantrene	1990	ARMC 26	300	S
carboplatin	Paraplatin	1986	ARMC 22	318	S
flutamide	Drogenil	1983	ARMC 19	318	S
fotemustine	Muphoran	1989	ARMC 25	313	S
heptaplatin/SK-2053R	Sunpla	1999	ARMC 35	348	S
lobaplatin	Lobaplatin	1998	DNP 12	35	S
lonidamine	Doridamina	1987	ARMC 23	337	S
miriplatin hydrate	Miripla	2010	DNP 23	17	S
nedaplatin	Aqupla	1995	ARMC 31	347	S
nilutamide	Anadron	1987	ARMC 23	338	S
olaparib	Lynparza	2014	DT 51(1)	56	S
oxaliplatin	Eloxatin	1996	ARMC 32	313	S
plerixafor hydrochloride	Mozobil	2009	DNP 22	17	S
pomalidomide	Pomalyst	2013	DT 50(1)	70	S
porfimer sodium	Photofrin	1993	ARMC 29	343	S
ranimustine	Cymerine	1987	ARMC 23	341	S
sobuzoxane	Parazolin	1994	ARMC 30	310	S
sorafenib	Nexavar	2005	DNP 19	45	S
vismodegib	Erivedge	2012	I 473491		S
zoledronic acid	Zometa	2000	DNP 14	24	S
alectinib hydrochloride	Alecensa	2014	DT 51(1)	56	S/NM
anastrozole	Arimidex	1995	ARMC 31	338	S/NM
apatinib mesylate	Aitan	2014	DT 51(1)	56	S/NM
bicalutamide	Casodex	1995	ARMC 31	338	S/NM
bortezomib	Velcade	2003	ARMC 39	345	S/NM
camostat mesylate	Foipan	1985	ARMC 21	325	S/NM
ceritinib	Zykadia	2014	DT 51(1)	55	S/NM
dasatinib	Sprycel	2006	DNP 20	27	S/NM
enzalutamide	Xtandi	2012	I 438422		S/NM
erlotinib hydrochloride	Tarceva	2004	ARMC 40	454	S/NM
fadrozole HCl	Afema	1995	ARMC 31	342	S/NM
gefitinib	Iressa	2002	ARMC 38	358	S/NM
imatinib mesilate	Gleevec	2001	DNP 15	38	S/NM
lapatinib ditosylate	Tykerb	2007	ARMC 43	475	S/NM
letrazole	Femara	1996	ARMC 32	311	S/NM
nilotinib hydrochloride	Tasigna	2007	ARMC 43	480	S/NM
pazopanib	Votrient	2009	DNP 23	18	S/NM
sunitinib malate	Sutent	2006	DNP 20	27	S/NM
temoporfin	Foscan	2002	I 158118		S/NM
toremifene	Fareston	1989	ARMC 25	319	S/NM
azacytidine	Vidaza	2004	ARMC 40	447	S*
capecitabine	Xeloda	1998	ARMC 34	319	S*
carmofur	Mifurol	1981	I 091100		S*
clofarabine	Clolar	2005	DNP 19	44	S*
decitabine	Dacogen	2006	DNP 20	27	S*
doxifluridine	Furtulon	1987	ARMC 23	332	S*
enocitabine	Sunrabin	1983	ARMC 19	318	S*
fludarabine phosphate	Fludara	1991	ARMC 27	327	S*
gemcitabine HCl	Gemzar	1995	ARMC 31	344	S*
mitoxantrone HCI	Novantrone	1984	ARMC 20	321	S*
nelarabine	Arranon	2006	ARMC 42	528	S*
pixantrone dimaleate	Pixuri	2012	I 197776		S*
tipiracil hydrochloride	Lonsurf	2014	DT 51(1)	58	S*
abarelix	Plenaxis	2004	ARMC 40	446	S*/NM
afatinib	Gilotrif	2013	DT 50(1)	69	S*/NM
axitinib	Inlyta	2012	I 38296		S*/NM
belinostat	Beleodaq	2014	DT 51(1)	56	S*/NM
bexarotene	Targretine	2000	DNP 14	23	S*/NM
bosutinib	Bosulif	2012	I 301996		S*/NM
cabozantinib S-malate	Cometriq	2012	I 379934		S*/NM
crizotinib	Xalkori	2011	DT 48(1)	45	S*/NM
dabrafenib mesilate	Tafinlar	2013	DT 50(1)	69	S*/NM
degarelix	Firmagon	2009	DNP 22	16	S*/NM
ibrutinib	Imbruvica	2013	DT 50(1)	71	S*/NM
idelalisib	Zydelig	2014	DT 51(1)	54	S*/NM
pemetrexed disodium	Alimta	2004	ARMC 40	463	S*/NM
ponatinib	Iclusig	2013	DT 50(1)	70	S*/NM
radotinib	Supect	2012	I 395674		S*/NM
raltiterxed	Tomudex	1996	ARMC 32	315	S*/NM
regorafenib	Stivarga	2012	I 395674		S*/NM
ruxolitinib phosphate	Jakafi	2011	DT 48(1)	47	S*/NM
tamibarotene	Amnoid	2005	DNP 19	45	S*/NM
temozolomide	Temodal	1999	ARMC 35	350	S*/NM
trametinib DMSO	Mekinist	2013	DT 50(1)	69	S*/NM
vandetanib	Caprelsa	2011	DT 48(1)	45	S*/NM
vemurafenib	Zeboraf	2011	DT 48(1)	45	S*/NM
vorinostat	Zolinza	2006	DNP 20	27	S*/NM
	Cervarix	2007	I 309201		V
autologous tumor cell-BCG	OncoVAX	2008	DNP 22	17	V
bcg live	TheraCys	1990	DNP 04	104	V
melanoma theraccine	Melacine	2001	DNP 15	38	V
vitespen	Oncophage	2008	DNP 22	17	V

Table 10. All Anticancer Drugs (Late 1930s to 12/31/2014) Organized Alphabetically by Generic Name within Source

generic name	year introduced	reference	page	source
131I-chTNT	2007	I 393351		B
alemtuzumab	2001	DNP 15	38	B
aldesleukin	1992	ARMC 25	314	B
bevacizumab	2004	ARMC 40	450	B
catumaxomab	2009	DNP 23	18	B
celmoleukin	1992	DNP 06	102	B
cetuximab	2003	ARMC 39	346	B
denileukin diftitox	1999	ARMC 35	338	B
H-101	2005	DNP 19	46	B
ibritumomab	2002	ARMC 38	359	B
interferon alfa2a	1986	I 204503		B
interferon, gamma-1a	1992	ARMC 28	332	B
interleukin-2	1989	ARMC 25	314	B
ipilimumab	2011	DT 48(1)	45	B
mobenakin	1999	ARMC 35	345	B
mogamulizumab	2012	I 433141		B
nimotuzumab	2006	DNP 20	29	B
nivolumab	2014	DT 51(1)	56	B
obinutuzumab	2013	DT 50(1)	70	B
ofatumumab	2009	DNP 23	18	B
panitumumab	2006	DNP 20	28	B
pegaspargase	1994	ARMC 30	306	B
pembrolizumab	2014	DT 51(1)	56	B
pertuzumab	2012	I 300439		B
racotumomab	2013	DT 50(1)	72	B
ramucirumab	2014	DT 51(1)	55	B
Rexin-G (trade name)	2007	I 346431		B
rituximab	1997	DNP 11	25	B
sipuleucel-T	2010	I 259673		B
tasonermin	1999	ARMC 35	349	B
teceleukin	1992	DNP 06	102	B
tositumomab	2003	ARMC 39	364	B
trastuzumab	1998	DNP 12	35	B
PICN (Trade Name)	2014	DT 51(1)	58	N
aclarubicin	1981	I 090013		N
actinomycin D	1964	FDA		N
angiotensin II	1994	ARMC 30	296	N
arglabin	1999	ARMC 35	335	N
asparaginase	1969	FDA		N
bleomycin	1966	FDA		N
carzinophilin	1954	Japan Antibiotics		N
chromomycin A3	1961	Japan Antibiotics		N
daunomycin	1967	FDA		N
doxorubicin	1966	FDA		N
homoharringtonine	2012	I 090682		N
ingenol mebutate	2012	I 328987		N
leucovorin	1950	FDA		N
masoprocol	1992	ARMC 28	333	N
mithramycin	1961	FDA		N
mitomycin C	1956	FDA		N
neocarzinostatin	1976	Japan Antibiotics		N
paclitaxel	1993	ARMC 29	342	N
paclitaxel nanopart (Abraxane)	2005	DNP 19	45	N
paclitaxel nanopart (Nanoxel)	2007	I 422122		N
paclitaxel nanopart (Genexol-PM)	2007	I 811264		N
pentostatin	1992	ARMC 28	334	N
peplomycin	1981	I 090889		N
romidepsin	2010	DNP 23	18	N
sarkomycin	1954	FDA		N
streptozocin	pre-1977	Carter		N
testosterone	pre-1970	Cole		N
trabectedin	2007	ARMC 43	492	N
vinblastine	1965	FDA		N
vincristine	1963	FDA		N
solamargines	1989	DNP 03	25	NB
abiratenone acetate	2011	DT 48(1)	44	ND
alitretinoin	1999	ARMC 35	333	ND
aminolevulinic-CO₂CH₃	2001	DNP 15	34	ND
amrubicin HCl	2002	ARMC 38	349	ND
belotecan hydrochloride	2004	ARMC 40	449	ND
bf-200 ala	2012	I 431098		ND
brentuximab vedotin	2011	DT 48(1)	45	ND
cabazitaxel	2010	I 287186		ND
calusterone	1973	FDA		ND
carfilzomib	2012	I 413092		ND
cladribine	1993	ARMC 29	335	ND
cytarabine ocfosfate	1993	ARMC 29	335	ND
dexamethasone	1958	FDA		ND
docetaxel	1995	ARMC 31	341	ND
dromostanolone	1961	FDA		ND
elliptinium acetate	1983	P091123		ND
epirubicin HCI	1984	ARMC 20	318	ND
eribulin	2010	I 287199		ND
estramustine	1980	FDA		ND
ethinyl estradiol	pre-1970	Cole		ND
etoposide	1980	FDA		ND
etoposide phosphate	1996	DNP 10	13	ND
exemestane	1999	DNP 13	46	ND
fluoxymesterone	pre-1970	Cole		ND
formestane	1993	ARMC 29	337	ND
fosfestrol	pre-1977	Carter		ND
fulvestrant	2002	ARMC 38	357	ND
gemtuzumab ozogamicin	2000	DNP 14	23	ND
hexyl aminolevulinate	2004	I 300211		ND
histrelin	2004	I 109865		ND
hydroxyprogesterone	pre-1970	Cole		ND
idarubicin hydrochloride	1990	ARMC 26	303	ND
irinotecan hydrochloride	1994	ARMC 30	301	ND
ixabepilone	2007	ARMC 43	473	ND
medroxyprogesterone acetate	1958	FDA		ND
megesterol acetate	1971	FDA		ND
methylprednisolone	1955	FDA		ND
methyltestosterone	1974	FDA		ND
mifamurtide	2010	DNP 23	18	ND
miltefosine	1993	ARMC 29	340	ND
mitobronitol	1979	FDA		ND
nadrolone phenylpropionate	1959	FDA		ND
norethindrone acetate	pre-1977	Carter		ND
pirarubicin	1988	ARMC 24	309	ND
pralatrexate	2009	DNP 23	18	ND
prednisolone	pre-1977	Carter		ND
prednisone	pre-1970	Cole		ND
talaporfin sodium	2004	ARMC 40	469	ND
temsirolimus	2007	ARMC 43	490	ND
teniposide	1967	FDA		ND
testolactone	1969	FDA		ND
topotecan HCl	1996	ARMC 32	320	ND
trastuzumab emtansine	2013	DT 50(1)	69	ND
triamcinolone	1958	FDA		ND
triptorelin	1986	I 090485		ND
valrubicin	1999	ARMC 35	350	ND
vapreotide acetate	2004	I 135014		ND
vindesine	1979	FDA		ND
vinflunine	2010	I 219585		ND
vinorelbine	1989	ARMC 25	320	ND
zinostatin stimalamer	1994	ARMC 30	313	ND
amsacrine	1987	ARMC 23	327	S
arsenic trioxide	2000	DNP 14	23	S
bisantrene hydrochloride	1990	ARMC 26	300	S
busulfan	1954	FDA		S
carboplatin	1986	ARMC 22	318	S
carmustine (BCNU)	1977	FDA		S
chlorambucil	1956	FDA		S
chlortrianisene	pre-1981	Boyd		S
cis-diamminedichloroplatinum	1979	FDA		S
cyclophosphamide	1957	FDA		S
dacarbazine	1975	FDA		S
diethylstilbestrol	pre-1970	Cole		S
flutamide	1983	ARMC 19	318	S
fotemustine	1989	ARMC 25	313	S
heptaplatin/SK-2053R	1999	ARMC 35	348	S
hexamethylmelamine	1979	FDA		S
hydroxyurea	1968	FDA		S
ifosfamide	1976	FDA		S
levamisole	pre-1981	Boyd		S
lobaplatin	1998	DNP 12	35	S
lomustine (CCNU)	1976	FDA		S
lonidamine	1987	ARMC 23	337	S
mechlorethanamine	1958	FDA		S
melphalan	1961	FDA		S
miriplatin hydrate	2010	DNP 23	17	S
mitotane	1970	FDA		S
nedaplatin	1995	ARMC 31	347	S
nilutamide	1987	ARMC 23	338	S
nimustine hydrochloride	pre-1981	Boyd		S
oxaliplatin	1996	ARMC 32	313	S
pamidronate	1987	ARMC 23	326	S
pipobroman	1966	FDA		S
plerixafor hydrochloride	2009	DNP 22	17	S
porfimer sodium	1993	ARMC 29	343	S
procarbazine	1969	FDA		S
ranimustine	1987	ARMC 23	341	S
razoxane	pre-1977	Carter		S
semustine (MCCNU)	pre-1977	Carter		S
sobuzoxane	1994	ARMC 30	310	S
sorafenib	2005	DNP 19	45	S
thiotepa	1959	FDA		S
triethylenemelamine	pre-1981	Boyd		S
zoledronic acid	2000	DNP 14	24	S
alectinib hydrochloride	2014	DT 51(1)	56	S/NM
anastrozole	1995	ARMC 31	338	S/NM
apatinib mesylate	2014	DT 51(1)	56	S/NM
bicalutamide	1995	ARMC 31	338	S/NM
bortezomib	2003	ARMC 39	345	S/NM
camostat mesylate	1985	ARMC 21	325	S/NM
dasatinib	2006	DNP 20	27	S/NM
enzalutamide	2012	I 438422		S/NM
erlotinib hydrochloride	2004	ARMC 40	454	S/NM
fadrozole HCl	1995	ARMC 31	342	S/NM
gefitinib	2002	ARMC 38	358	S/NM
imatinib mesilate	2001	DNP 15	38	S/NM
lapatinib ditosylate	2007	ARMC 43	475	S/NM
letrazole	1996	ARMC 32	311	S/NM
nafoxidine	pre-1977	Carter		S/NM
nilotinib hydrochloride	2007	ARMC 43	480	S/NM
pazopanib	2009	DNP 23	18	S/NM
sunitinib malate	2006	DNP 20	27	S/NM
tamoxifen	1973	FDA		S/NM
temoporfin	2002	I 158118		S/NM
toremifene	1989	ARMC 25	319	S/NM
aminoglutethimide	1981(?)	FDA		S*
azacytidine	2004	ARMC 40	447	S*
capecitabine	1998	ARMC 34	319	S*
carmofur	1981	I 091100		S*
clofarabine	2005	DNP 19	44	S*
cytosine arabinoside	1969	FDA		S*
decitabine	2006	DNP 20	27	S*
doxifluridine	1987	ARMC 23	332	S*
enocitabine	1983	ARMC 19	318	S*
floxuridine	1971	FDA		S*
fludarabine phosphate	1991	ARMC 27	327	S*
fluorouracil	1962	FDA		S*
ftorafur	1972	FDA		S*
gemcitabine HCl	1995	ARMC 31	344	S*
mercaptopurine	1953	FDA		S*
methotrexate	1954	FDA		S*
mitoxantrone HCI	1984	ARMC 20	321	S*
nelarabine	2006	ARMC 42	528	S*
pixantrone dimaleate	2012	I 197776		S*
thioguanine	1966	FDA		S*
tipiracil hydrochloride	2014	DT 51(1)	58	S*
uracil mustard	1966	FDA		S*
abarelix	2004	ARMC 40	446	S*/NM
afatinib	2013	DT 50(1)	69	S*/NM
axitinib	2012	I 38296		S*/NM
belinostat	2014	DT 51(1)	56	S*/NM
bexarotene	2000	DNP 14	23	S*/NM
bosutinib	2012	I 301996		S*/NM
cabozantinib S-malate	2012	I 301996		S*/NM
crizotinib	2012	I 379934		S*/NM
dabrafenib mesilate	2011	DT 48(1)	45	S*/NM
degarelix	2009	DNP 22	16	S*/NM
ibrutinib	2013	DT 50(1)	71	S*/NM
idelalisib	2014	DT 51(1)	54	S*/NM
pemetrexed disodium	2004	ARMC 40	463	S*/NM
ponatinib	2013	DT 50(1)	70	S*/NM
radotinib	2012	I 395674		S*/NM
raltiterxed	1996	ARMC 32	315	S*/NM
regorafenib	2012	I 395674		S*/NM
ruxolitinib phosphate	2011	DT 48(1)	47	S*/NM
tamibarotene	2005	DNP 19	45	S*/NM
Temozolomide	1999	ARMC 35	350	S*/NM
trametinib DMSO	2013	DT 50(1)	69	S*/NM
vandetanib	2011	DT 48(1)	45	S*/NM
vemurafenib	2011	DT 48(1)	45	S*/NM
vorinostat	2006	DNP 20	27	S*/NM
autologous tumor cell-BCG	2008	DNP 22	17	V
bcg live	1990	DNP 04	104	V
Cervarix (trade name)	2007	I 309201		V
melanoma theraccine	2001	DNP 15	38	V
vitespen	2008	DNP 22	17	V

Table 11. Antidiabetic Drugs from 01.01.1981 to 12.31.2014 Organized Alphabetically by Generic Name within Source/Year

generic name	trade name	year introduced	volume	page	source
isophane insulin	Humulin N	1982	I 091583		B
porcine isophane insulin	Pork Insulatard	1982	I 302757		B
human insulin Zn suspension	Humulin L	1985	I 302828		B
human insulin zinc suspension	Humulin Zn	1985	I 091584		B
soluble insulin	Velosulin BR	1986	I 091581		B
human neutral insulin	Novolin R	1991	I 182551		B
hu neutral insulin	Insuman	1992	I 255451		B
mecasermin	Somazon	1994	DNP 08	28	B
insulin lispro	Humalog	1996	ARMC 32	310	B
porcine neutral insulin	Pork Actrapid	1998	I 302749		B
insulin aspart	NovoRapid	1999	DNP 13	41	B
insulin glargine	Lantus	2000	DNP 14	19	B
insulin aspart/IA protamine	NovoMix 30	2001	DNP 15	34	B
insulin determir	Levemir	2004	DNP 18	27	B
insulin glulisine	Apidra	2005	DNP 19	39	B
oral insulin	Oral-lyn	2005	DNP 19	39	B
pulmonary insulin	Exubera	2006	DNP 20	23	B
insulin degludec/insulin aspar	DegludecPlus	2012	I 419438		B
insulin degludec	Degludec	2012	I 470782		B
pulmonary insulin	Afrezza	2014	DT 51(1)	45	B
albiglutide	Eperzan	2014	DT 51(1)	45	B
dulaglutide	Trulicity	2014	DT 51(1)	45	B
voglibose	Basen	1994	ARMC 30	313	N
acarbose	Glucobay	1990	DNP 03	23	ND
miglitol	Diastabol	1998	ARMC 34	325	ND
extenatide	Byetta	2005	DNP 19	40	ND
triproamylin acetate	Normylin	2005	DNP 19	40	ND
liraglutide	Victoza	2009	DNP 23	13	ND
lixisenatide	Lyxumia	2013	DT 50(1)	60	ND
glimepiride	Amaryl	1995	ARMC 31	344	S
repaglinide	Prandin	1998	ARMC 34	329	S
pioglitazone NCl	Actos	1999	ARMC 35	346	S
mitiglinide calcium hydrate	Glufast	2004	ARMC 40	460	S
epalrestat	Kinedak	1992	ARMC 28	330	S/NM
troglitazone	Rezulin	1997	ARMC 33	344	S/NM
rosiglitazone maleate	Avandia	1999	ARMC 35	348	S/NM
sitagliptin	Januvia	2006	DNP 20	23	S/NM
vildagliptin	Galvus	2007	ARMC 43	494	S/NM
saxagliptin	Onglyza	2009	DNP 23	13	S/NM
alogliptin benzoate	Nesina	2010	I 405286		S/NM
linagliptin	Tradjenta	2011	DT 48(1)	39	S/NM
teneligliptin hydrobromide	Tenelia	2012	I 343981		S/NM
anagliptin	Suiny	2012	I 426247		S/NM
tolrestat	Alredase	1989	ARMC 25	319	S/NM
nateglinide	Starsis	1999	ARMC 35	344	S*
dapagliflozin	Forxiga	2012	I 356099		S*/NM
canagliflozin	Invokana	2013	DT 50(1)	60	S*/NM
empagliflozin	Jardiance	2014	DT 51(1)	45	S*/NM
ipragliflozin proline	Suglat	2014	DT 51(1)	45	S*/NM
tofogliflozin	Apleway	2014	DT 51(1)	45	S*/NM
luseogliflozin	Lusefi	2014	DT 51(1)	45	S*/NM

Disease Area Breakdowns

It should be noted before proceeding with this and subsequent sections that we altered some of the “disease nomenclature terminology”, for example, rolling in all antidiabetic treatments under one category rather than subdividing into types 1 and 2. Thus, a direct comparison of Table 2 in this review with its predecessor tables needs to take such modifications into account. Inspection of Table 2 demonstrates that, overall, the major disease areas that have been investigated (in terms of numbers of drugs approved) in the pharmaceutical industry continue to be infectious diseases (microbial, parasitic, and viral), cancer, hypertension, antidiabetic, and inflammation, all with over 50 approved drug therapies. It should be noted, however, that the numbers of approved drugs/disease do not correlate with the “value” as measured by sales. For example, the best-selling drug of all at the moment is atorvastatin (Lipitor), a hypocholesterolemic descended directly from a microbial natural product, which sold over (U.S.) $11 billion in 2004, and, if one includes sales by Pfizer and Astellas Pharma over the 2004 to 2014 time frames, sales have hovered in the range (U.S.) $12–14 billion depending upon the year. However, this figure is almost sure to be eclipsed in short order by the new drugs approved for hepatitis C treatments such as sofosbuvir (14), which is a masked nucleotide, but is currently classified by us as an “S*”, although it is obviously based upon an NP scaffold.

Anti-infectives in General

This is the major category by far including antiviral vaccines, with 326 (25%) of the total drug entities (1328 for indications ≥4; Table 2) falling into this one major human disease area. On further analysis (Tables 7 and 8), the influence of biologicals and vaccines in this disease complex is such that only 22% are synthetic in origin (Table 7). If one considers only small molecules (reducing the total by 105 to 221; Table 8), then the synthetic figure goes up to 33%, marginally greater than in our 2012 report. (4) As reported previously, (1-4) these synthetic drugs tend to be of two basic chemotypes, the azole-based antifungals and the quinolone-based antibacterials.

Anitbacterial Agents

Nine small-molecule drugs were approved in the antibacterial area from January 2011 to December 2014. One, fidaxomycin (15), was classified as an “N”; four were classified as “ND”, with the first, ceftaroline (16), being a semisynthetic cephalosporin, the second being another cephalosporin derivative, cetolozane (17a) in combination with the well-known β-lactamase inhibitor tazobactam (17b); the third was the modified glycopeptide dalvabancin (18); and the fourth was another of this class, oritavancin (19). The two synthetic molecules included the first novel anti-TB scaffold for many years, bedaquiline (20), and another “floxacin”, finafloxacin (21). Overall, in the antibacterial area, as shown in Table 7, small molecules account for 112 agents, with “N” and “ND” compounds accounting for just over 73% of the approved agents.

What should make biomedical scientists and physicians involved in antibacterial research in academia or industry very nervous is the recent report from Liu et al., (124) in the journal Lancet Infectious Disease in the middle of November 2015, where they reported that the class of compounds used effectively as the last resort (the peptidic colistins) now have a resistance determinant known as mcr-1 appearing in microbes in treated patients and animals.

Antifungal Agents

In this area, two drugs were approved in the 2011 to 2014 time frame. These were two synthetic compounds, one the azole antifungal efinaconazole (22) ,and the other, tavaborole (23), is the first example of this novel skeleton containing boron. It should be noted, however, that a natural product, boromycin, a complex macrolide first isolated from Streptomyces antibioticus, was reported by the Zahner group (125) in 1967 with antibacterial activity, and then in 1996, it was reisolated by Kohno et al. (126) as an anti-HIV agent from an unspeciated streptomycete. Its probable mode of action is as a specialized ionophore. In contrast to the antibacterial agents, the majority of antifungal agents in the years from 1981 to 2014 are synthetic in origin, as can be seen from inspection of Table 8, with 28 of the 31 approved drugs (90%) being classified as other than natural product based. The paucity of natural product sources can be seen in the modern treatment regimens that still use agents such as amphotericin and griseofulvin, which are both listed in the Integrity database as being launched in 1958.

Antiviral Drugs

In this area, as mentioned earlier, a significant number of the agents are vaccines, predominately directed against various serotypes of influenza, as would be expected from the avian flu outbreaks. In the time frame 2011 to 2014, and looking only at small molecules, 16 drugs were approved for basically two viral diseases, HIV, as would be expected, and hepatitis C (HCV), with drugs directed against specific RNA polymerases and HCV proteases. There were no drugs formally from the “N*” categories, but eight fell into the “S*” or “S*/NM” classifications. In 2011, two “S*/NM” drugs were approved, boceprevir (24) and telaprevir (25), both directed against HCV proteases. None in this classification were approved in 2012. However, as mentioned above, in 2013 one “S*” drug, sofosbuvir (14), was approved for use against HCV. This particular drug, a “masked nucleotide”, has the potential to become the best-selling drug of all time, as it currently is the only drug that cures HCV infections in roughly two months. However, its current nominal cost for this treatment is close to $90 000 per patient. The only other curative treatment for patients with HCV once a severe stage is reached is a liver transplant. Also in the same year, the “S*/NM” classified drug simeprevir (26) was approved and acts against HCV proteases.

In 2014, however, there was a relative flood of approvals including one very unusual action by the FDA. The outlier, before this action is covered, was the approval of the anti-influenza small-molecule drug favipiravir (27). In 2014, the FDA approved a combination therapy known as Viekira Pak against HCV proteases. Normally, this combination therapy would not have been included in the listings, but in this case, the FDA effectively approved two clinical candidates, ombitasvir (28), then in phase II, and paritaprevir (29), then in phase III, in a combination with the 1996-approved drug ritonavir (30), also a compound falling into the “S*/NM” classification. Finally, under this category, the HCV protease inhibitor vaniprevir (31) was also approved in 2014.

If we now move to the synthetic area for the time period 2011 to 2014, there were five drugs in the “S” classification and three in the “S/NM” classification. In the “S” classification, there was one approval in 2011 of rilpivirine (32), a reverse-transcriptase inhibitor, and none in 2012, but in 2013 there were two drugs approved as HIV integrase inhibitors, dolutegravir (33) and elvitegravir (34). Then, in 2014, two more anti-HCV drugs, daclatasvir (35) and dasabuvir (36), were approved. Under the “S/NM” classification, three drugs were approved, none in 2011 and 2012, one [cobicistat (37)] in 2013 as an HIV protease inhibitor, and then two anti-HCV drugs in 2014, asunaprevir (38) and ledipasvir (39). The latter drug is unusual in that it is part of a combination therapy with sofosbuvir (14) under the trade name Harvoni and thus may be in direct competition with the earlier drug.

To sum up, in contrast to the antibacterial and antifungal areas, in the antiviral case, as shown in Table 7, small molecules accounted for 64 drugs, with only four (or 6%) in the 34 years of coverage falling into the “ND” category. However, as mentioned earlier, we have consistently placed modified nucleosides, peptidomimetics, etc., into the “S*” or “S*/NM” category. If these are added to the four drugs mentioned above, then the other than synthetic molecules account for 45, or 70% overall.

Disease Areas without Current Natural Product Drugs

As reported in our earlier analyses, (1-4) there are still disease areas where at the present time the available drugs are totally synthetic in origin. These include antihistamines, diuretics, and hypnotics for indications with four or more approved drugs (cf., Table 2), and, as found in the earlier reviews, there are still a substantial number of indications in which there are three or less approved drugs that are also totally synthetic.

Disease Areas with “*/NM” Classified Drugs

As mentioned in our earlier reviews, (2-4) due to the introduction of the “NM” subcategory, indications such as antidepressants, bronchodilators, and cardiotonics now have substantial numbers that, although formally “S” or “S*”, fall into the “S/NM” or “S*/NM” subcategory, as the information in the literature points to their interactions at active sites as competitive inhibitors.

Anticancer Drugs 1981–2014

In this disease area (Table 9), in the time frame covered (01/1981–12/2014) there were 174 NCEs in total, with the number of nonbiologicals, aka small molecules, being 136 (78%), effectively the same percentage as the value of 77% in the last review. (4) Using the total of 136 as being equal to 100%, the breakdown was as follows, with the values from the last review inserted for comparison: “N” (17, 13% {11, 11%}), “NB” (1, 1% {1, 1%}), “ND” (38, 28% {32, 32%}), “S” (23, 17%, {20, 20%}), “S/NM” (20, 15% {16, 16% }), “S*” (13, 10% {11, 11%}), and “S*/NM” (24, 18% {8, 8%}). Thus, using our criteria, only 17% of the total number of small-molecule anticancer drugs were classifiable into the “S” (synthetic) category. Expressed as a proportion of the nonbiologicals/vaccines, then 113 of 136 (83%) were either natural products per se or were based thereon, or mimicked natural products in one form or another.

From a natural products perspective, in the antitumor area there were some significant aspects in the four years from 2011 to 2014. Another nanoparticular, paclitaxel (PICN), was approved in India in 2014 as the fourth variation on this drug delivery approach, and two plant-derived agents, omacetaxine mepesuccinate (homoharringtonine) (40) and ingenol mebutate (41) (as an agent against actinic keratosis, a precancerous condition, that if untreated usually leads to a melanoma), were approved in 2012 by the FDA. The history of homoharringtonine was described by Camp (127) and Kantarjian et al., (128) and that of the diterpenoid ingenol by a number of publications from Baran’s group, (129-131) all showing the levels to which researchers had gone to develop these agents. From an “ND” aspect, abiraterone (132) (42) was approved in 2011 with Adcetris, a dolastatin 10 derivative linked to an anti-CD33 monoclonal, (133, 134) being approved the same year. In 2012, the aminolaevulinic acid conjugate Ameluz was approved for photodynamic therapy, (135) and the same year saw the approval of carfilzomib (136) (43), the proteasome derivative that evolved from the work of Craig Crews (137) at Yale University. Then, in 2013 the maytansine–herceptin linked monoclonal antibody Kadcyla was approved. (138, 139) From the “S*” category, pixantrone (140) (44) was approved in 2012, with the uridine derivative tipiracil (141) (45) approved in 2014. Inspection of Table 9 shows that a significant number of PTKs were also approved in these years, with the numbers being predominately under the “S*/NM” category, although the HDAC inhibitor belinostat (142) (46) also was approved in 2014 and fell into the same category; thus the influence of natural products in the synthetic arena is still obvious.

Anticancer Drugs, Late 1930s to 2014

In this current review, we have continued as in our previous contributions (2-4) to reassess the influence of natural products and their mimics as leads to anticancer drugs from the beginnings of antitumor chemotherapy in the very late 1930s to the early 1940s. Using data from the FDA listings of antitumor drugs, plus our earlier data sources and with help from colleagues based worldwide, we have been able to specify the years in which all but 17 of the 246 drugs listed in Table 10 were approved. We then identified these 17 agents by inspection of three time-relevant textbooks on antitumor treatment, (103-105) and these were added to the overall listings using the names of the lead authors as the source citation.

Inspection of Figure 10 and Table 10 shows that, over the whole category of anticancer drugs approved worldwide, the 246 approved agents can be categorized as follows, with the figures for the 2012 review (4) (n = 206) being included for comparison: “B” (33, 13% {26; 13%}), “N” (30, 12% {27; 13%}), “NB” (1, 1% {1; 1%}), “ND” (62, 25% {57; 28%}), “S” (47, 19% {44; 21%}), “S/NM” (22, 9% {18; 9%}), “S*” (22, 9% {20; 10%}), “S*/NM” (24, 10% {8; 4%}), and “V” (5, 2% {5; 2%}). Removing the high-molecular-weight materials (biologicals and vaccines) reduces the overall number to 207 (100%). If we then use the number of nonsynthetics but include the naturally inspired agents (i.e., “N”, “ND”, “S/NM”, “S*”, “S*/NM”), this number is 160, or 77% of the total small molecules (having removed categories “B”, “NB”, and “V” from the overall total), effectively the same percentage as the 75% figure from the 2012 review. (4) If the two “/NM” categories are also removed, then the figure drops to 114, or 55%, compared to the 60% in our earlier reviews. This can be attributed to the large number of protein kinase inhibitors that fell into the “/SM” classifications in the last four years, thus increasing the denominator for small molecules. Etoposide phosphate and various nanopaticle formulations of Taxol have been included for the sake of completeness. It should again be pointed out that the 17 antitumor drugs shown on the right in Figure 11 are not duplicated in the rest of the bar graph; we simply have not been able to locate accurate data on their initial approval dates.

Small-Molecule Antidiabetic Drugs

In the case of these drugs and looking only at small molecules for both diabetes I and II, the numbers since our last review have increased by 10 to 29 (Table 11). One, lixisentide (47), approved in 2013, fell into the “ND” classification, as it, like extenatide (Byetta), is a derivative of exendin-4. (143) Under the classification “S/NM”, there were three approvals of drugs all targeted at the same enzyme complex, dipeptidyl peptidase IV (DPP-IV). The first was linagliptin (144) (48) in 2011, with the next two in 2012, teneligliptin (145) (49) and anagliptin (146) (50).

However, for “pride of place”, one cannot beat the six sodium-dependent glucose transporter inhibitors (SGLTi’s) that were approved between 2012 and 2014, all falling into the “S*/NM” classification. In 2012, dapagliflozin (147) (51) was approved in the EU; this was followed in 2013 by canagliflozin (148) (12) in the USA. In 2014, there were no less than four drugs launched all directed against this target. In alphabetical order, they were empaglifozin (149) (52) in the EU and the USA almost simultaneously, with the next three, ipragliflozin cocrystallized with l-proline (150) (53), luseogliflozin (151) (54), and tofoglflozin (152) (55), launched in Japan.

Discussion

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In contrast to the situation referred to in our previous three reviews, (2-4) the decline or leveling of the output of the R&D programs of the pharmaceutical companies may have begun to turn around when compared to earlier years in the 21st century. The figures for drugs of all types had dropped in 2006 to 40 NCEs launched, of which 19 (48%) were classified in the “other than small molecules”, being in the “B/V” categories.

Increases in Biologicals and Vaccines from 2007

In the eight years 2007–2014 as shown in the bar graph in Figure 2, the corresponding figures are as follows. In 2007, there were 44 NCEs launched, with 18 (41%) classified as “B/V”. In 2008, 38 NCEs were launched, with 14 (37%) classified as “B/V”. In 2009, 42 NCEs were launched, with 18 (43%) classified as “B/V”. Then, in 2010, there was a dip, where only 33 NCEs were launched, with 13 (39%) classified as “B/V”. In 2011, there was an increase of 1 to 34, with 7 (20%) classified as “B/V”; however the proportion of small molecules increased that year, so the divisor increased. In 2012, there was almost a doubling of NCEs to 60, but 25 (42%) fell into the “B/V” categories. This increase in 2012 in approved vaccines was due predominately to “avian influenza” treatments. In 2013, there was a drop to 47 NCEs, with 16 (34%) still attributable to the “B/V” categories. However, in 2014, the trend line for small-molecule NCEs began to move upward again, with 65 NCEs approved, of which 21 (32%) were in the “B/V” categories. Thus, one can see that, overall, of the total of 363 NCEs in these years, 132 (36%) fell into the “B/V” categories. However, as shown in Figure 7, although there were fluctuations in the overall numbers, a reasonable to substantial proportion of all small-molecule NCEs fell into the “N*” category; thus even in these days of advances in immunopharmacology-based treatments, natural-product-based small molecules are still in play.

Potential Sources of Natural Product Skeletons

Although combinatorial chemistry continues to play a major role in the drug development process, as mentioned earlier, it is noteworthy that the trend toward the synthesis of complex natural-product-like libraries has continued. Even including these newer methodologies, we still cannot find other de novo combinatorial compounds approved anywhere in the world than the three compounds (1–3) referred to earlier, although reliable data are still not available on approvals in Russia and the People’s Republic of China at this time.

A rapid analysis of the small-molecule entities approved from 2011 to 2014 has indicated that there were significant numbers of antitumor, antibacterial, and antifungal agents approved, as mentioned above. The antibacterial compounds were either NPs or based on their skeletons, although, as is now, “the norm” antifungal agents were synthetic in origin.

Genomic Sources of Novel NP Skeletons

If one asks the question “where will novel natural product skeletons come from in the future?”, the answer, we think, is from the massive amounts of genetic information now being amassed from microbial sources. There was always the comment made in previous years that only a very small proportion of the microbial world can be fermented. However, two excellent papers in the last two years have shown that genetic information can be “abstracted” from as yet uncultured microbes from sessile marine organisms. These were the “tour de force” by the Piel group in 2014, demonstrating that 31 of the then 32 known bioactive metabolites from the sponge Theonella swinhoei Y (yellow variant) were produced by a totally novel biochemical mechanism in an as yet uncultured microbe. (153) This was followed a year later by proof in the middle of 2015 from the Sherman group (154) that the source of the approved antitumor drug Yondelis, or Et743, is an as yet uncultured microbe in the tunicate Ecteinascidia turbinata, from which the Et743 complex was first isolated. Does this mean only from invertebrate sources? No, we consider that the information now coming from investigations on free-living microbes from often extreme sources (cold, hot, high pressure, etc.) will also provide novel skeletons for further work. (5, 8-11)

Similarly, if one moves to the plant kingdom, there is now a significant volume of published work that indicates that a fair number of what were thought to be “plant-derived” natural products are in fact produced “in part” and in some cases, such as maytansine, totally (155, 156) by interactions with endophytic microbes, frequently fungi. We currently say “in part” because the evidence for total production only by the isolated microbe is not yet finalized, and one cannot rule out horizontal gene transfer at this moment. However, the recent work by the Oberlies group (157) on the production of silybins by an endophytic fungus from the leaves of the milk thistle Silybum marianum demonstrated that these metabolites were produced by the isolated fungus when supplemented by a sterilized extract from the plant, a supplementation strategy well known in the days of antibiotic discovery but generally not used today by newer investigators studying these types of systems. People interested in this aspect of microbiology should also read the recent article from the Spiteller group demonstrating the production of cyclopeptides by a Fusarium species as “cross-talk” agents in plants, as this demonstrates the type of interaction we are referring to. (158)

Very recently, a series of reviews in the journal Natural Product Reports have further demonstrated the capabilities of modern techniques to help unlock the genomes of both cultivatable and “as yet uncultured” microbes from all sources. These should be read in conjunction with the articles referred to above on microbes isolated from marine invertebrates and plants, since together these aptly demonstrate the new technologies that can be brought to bear on the search for novel scaffolds from nature. (159-162)

In the period since our last review, other authors prominent in the natural product community have also published excellent reviews on natural products as drugs, (163, 164) and these, together with the review by Butler et al., (165) on natural product-based compounds in clinical trials, should also be read in conjunction with this review. In addition there were two very interesting reviews on small molecules, including natural products and close relatives, as protein–protein interaction inhibitors, which we also recommend reading to see how the role of NPs has expanded. (166, 167)

That synthetic chemists are not letting opportunities go by can be seen from the 2014 essay by Nicolaou (168) and a series of papers that cover synthetic approaches to the new drugs from 2009 to 2013. (169-173) It is highly probable that in the near future totally synthetic variations on complex natural products will be part of the therapeutic arsenal used by physicians. One has only to look at the extremely elegant syntheses of complex natural products reported recently by Baran and his co-workers to visualize the potential of coupling very active and interesting natural products with the skills of synthetic chemists in academia and industry. (131)

Two recent papers of interest to drug discovery and development that are quite relevant to the discussion are as follows. The first, which is quite sobering to read, intimates, with data, that the actual productivity of the pharmaceutical industry from a development aspect is lower than is evident from the press releases and other outlets that are often used to demonstrate success. (174) The second may be quite beneficial as far as natural products and/or their derivatives are concerned, as it now appears that phenotypic screening using high-content methodologies may be making a comeback over “targeted screening systems”. (175)

It is often not fully appreciated that the major hurdle in bringing a natural-product-based complex molecule to market is not the isolation, basic semisynthesis, or total synthesis, but the immense supply problems faced by process chemists in translating research laboratory discoveries to commercial items. Some recent examples of how these problems were overcome with natural products or their derivatives are given in a recent short review by one of the present authors. (176)

In this review, as we stated in 2003, 2007, and 2012, (2-4) we have yetagain demonstrated that natural products play a dominant role in the discovery of leads for the development of drugs for the treatment of human diseases. As we mentioned in earlier articles, some of our colleagues argued (though not in press, only in personal conversations at various fora) that the introduction of categories such as “S/NM” and “S*/NM” may well cause an overstatement of the role played by natural products in the drug discovery process. On the contrary, we would still argue that these further serve to illustrate the inspiration provided by Nature to receptive organic chemists in devising ingenious syntheses of structural mimics to compete with Mother Nature’s longstanding substrates. Even if we discount these categories, the continuing and overwhelming contribution of natural products to the expansion of the chemotherapeutic armamentarium is clearly evident, as demonstrated in Figures 6 and 7, and as we stated in our earlier papers, much of Nature’s “treasure trove of small molecules” remains to be explored, particularly from the marine and microbial environments.

To us, a multidisciplinary approach to drug discovery, involving the generation of truly novel molecular diversity from natural product sources, combined with total and combinatorial synthetic methodologies and including the manipulation of biosynthetic pathways, will continue to provide the best solution to the current productivity crisis facing the scientific community engaged in drug discovery and development.

Finally, the award of half of the 2015 Nobel Prize for Physiology or Medicine to Drs. Ŏmura and Campbell for their discovery and development of the avermectin/ivermectin complexes, with the other half being awarded to Prof. Tu for her discovery and development of artemisinin, is truly excellent news for the general public, as they may now begin to understand where these significant drugs were sourced. Two very recent publications cover some of the work that led to the awarding of this Nobel prize. The first by McKerrow (177) is a short description of the work performed by the three scientists, and the second, by Wang et al., (178) demonstrates the multiplicity of targets in the malaria parasite Plasmodium falciparum for artemisinin, none of which would have been recognized but for this agent.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.5b01055.

The drug data set (PDF)

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Author Information

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Corresponding Author
- David J. Newman - NIH Special Volunteer, Wayne, Pennsylvania 19087, United States; Email: [email protected]
Author
- Gordon M. Cragg - NIH Special Volunteer, Bethesda, Maryland 20814, United States
Notes
The authors declare no competing financial interest.
No external funding was provided to the authors from any source. All analyses of data were performed subsequent to the formal retirement of the corresponding author from the NCI on January 10, 2015. Both authors, though retired from NCI, are still NIH Special Volunteers.

References

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This article references 178 other publications.

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A review, with 38 refs., highlighting the invaluable role that natural products have played, and continue to play, in the drug discovery process, particularly in the areas of cancer and infectious diseases.
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A review. This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 yr from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compds. has been introduced, using the concept of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small mol., new chem. entities that are non-synthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are based on the serotonin mol. or derivs. thereof. Finally, although combinatorial techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of a no. of recently approved agents, we have not been able to identify a de novo combinatorial compd. approved as a drug in this time frame.
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Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461– 477 DOI: 10.1021/np068054v
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Natural Products as Sources of New Drugs over the Last 25 Years
Newman, David J.; Cragg, Gordon M.
Journal of Natural Products (2007), 70 (3), 461-477CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
A review. This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small mols., 73% are other than "S" (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 25 plus year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311– 335 DOI: 10.1021/np200906s
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Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
Newman, David J.; Cragg, Gordon M.
Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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Cragg, G. M.; Newman, D. J. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 3670– 3695 DOI: 10.1016/j.bbagen.2013.02.008
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Natural products: A continuing source of novel drug leads
Cragg, Gordon M.; Newman, David J.
Biochimica et Biophysica Acta, General Subjects (2013), 1830 (6), 3670-3695CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
A review. Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chem. (late 1980s), shifted the focus of drug discovery efforts from Nature to the lab. bench. This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technol. and genome mining. The knowledge gained has allowed unknown mols. to be identified. These novel bioactive structures can be optimized by using combinatorial chem. generating new drug candidates for many diseases. The advent of genetic techniques that permitted the isolation /expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The nos. of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these nos. to the no. of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.
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Newman, D. J.; Giddings, L.-A. Phytochem. Rev. 2014, 13, 123– 137 DOI: 10.1007/s11101-013-9292-6
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Natural products as leads to antitumor drugs
Newman, David J.; Giddings, Lesley-Ann
Phytochemistry Reviews (2014), 13 (1), 123-137CODEN: PRHEBS; ISSN:1568-7767. (Springer)
A review. The discussion in this short review emphasizes that the main and future source of novel natural products as leads to antitumor agents is probably in the areas of biol. that cannot be seen, i.e. the microbial world. The review discusses the role of microbes in the prodn. of secondary metabolites that were initially thought to be from marine invertebrates and goes on to discuss the potential for a no. of known anticancer agents isolated from plant sources to actually be the products of a microbe-plant interaction and finishes with a discussion of the potential of microbial "cryptic clusters" as sources of novel agents/leads to antitumor treatments.
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Newman, D. J.; Cragg, G. M. In Macrocycles in Drug Discovery; RSC Drug Discovery Series No. 40; Levin, J., Ed.; Royal Society of Chemistry: Cambridge, UK, 2014; pp 1– 36.
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Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Terrestrial Extremophiles; Springer: Heidelberg, 2015.
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Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Marine Extremophiles; Springer: Heidelberg, 2015.
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Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Extremophiles, Genomic Studies; Springer: Heidelberg, 2015.
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Newman, D. J.; Cragg, G. M.; Kingston, D. G. I. In The Practice of Medicinal Chemistry, 4th ed.; Wermuth, C. G.; Aldous, D.; Raboisson, P.; Rognan, D., Eds.; Elsevier: Amsterdam, 2015; pp 101– 139.
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Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740– 6741 DOI: 10.1021/ja016093h
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Use of Biomimetic Diversity-Oriented Synthesis to Discover Galanthamine-Like Molecules with Biological Properties beyond Those of the Natural Product
Pelish, Henry E.; Westwood, Nicholas J.; Feng, Yan; Kirchhausen, Tomas; Shair, Matthew D.
Journal of the American Chemical Society (2001), 123 (27), 6740-6741CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A library of mols. based on galanthamine was synthesized using solid-phase biomimetic reactions. The compds. were screened, and secramine (I) was found to be a potent inhibitor of VSVG-GFP movement from the Golgi app. to the plasma membrane.
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Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867– 3870 DOI: 10.1039/b310752n
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Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46– 58 DOI: 10.1002/anie.200300626
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A planning strategy for diversity-oriented synthesis
Burke, Martin D.; Schreiber, Stuart L.
Angewandte Chemie, International Edition (2004), 43 (1), 46-58CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chem., which aim to access precise or dense regions of chem. space, diversity-oriented synthesis (DOS) populates chem. space broadly with small-mols., having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small mols. having skeletal and stereochem. diversity with defined coordinates in chem. space. Ideally, these pathways also yield compds. having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the mols. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic anal. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic anal. This anal. facilitates synthetic planning, communication, and teaching in this evolving discipline.
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Zhonghong, G.; Reddy, P. T.; Quevillion, S.; Couve-Bonnaire, S.; Ayra, P. Angew. Chem., Int. Ed. 2005, 44, 1366– 1368 DOI: 10.1002/anie.200462298
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Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362– 370 DOI: 10.1016/j.cbpa.2010.03.018
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Current strategies for diversity-oriented synthesis
Dandapani, Sivaraman; Marcaurelle, Lisa A.
Current Opinion in Chemical Biology (2010), 14 (3), 362-370CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
A review. Compds. accessed through diversity-oriented synthesis (DOS) are showing promise in modulating the activities of several targets that are currently considered undruggable'. Recently many new DOS pathways have been developed employing multi-component reactions, cycloaddns., ring-closing metathesis and tandem processes. Functional group pairing and build/couple/pair' strategies have been described as a means for generating structural diversity. Efforts have also been directed towards developing DOS libraries based on privileged scaffolds. Recent studies have provided several compelling examples for the utility of DOS compds. for producing novel biol. probes and application of DOS in the context of drug discovery is extremely appealing.
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Reayi, A.; Arya, P. Curr. Opin. Chem. Biol. 2005, 9, 240– 247 DOI: 10.1016/j.cbpa.2005.04.007
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Natural product-like chemical space: search for chemical dissectors of macromolecular interactions
Reayi, Ayub; Arya, Prabhat
Current Opinion in Chemical Biology (2005), 9 (3), 240-247CODEN: COCBF4; ISSN:1367-5931. (Elsevier Ltd.)
A review. Macromol. interactions (i.e. protein-protein or DNA/RNA-protein interactions) play important cellular roles, including cellular communication and programmed cell death. Small-mol. chem. probes are crucial for dissecting these highly organized interactions, for mapping their function at the mol. level and developing new therapeutics. The lack of ideal chem. probes required to understand macromol. interactions is the missing link in the next step of dissecting such interactions. Unfortunately, the classical combinatorial-chem. community has not successfully provided the required probes (i.e. natural product inspired chem. probes that are rich in stereochem. and three-dimensional structural diversity) to achieve these goals. The emerging area of diversity-oriented synthesis (DOS) is beginning to provide natural product-like chem. probes that may be useful in this arena.
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Keller, T. H.; Pichota, A.; Yin, Z. Curr. Opin. Chem. Biol. 2006, 10, 357– 361 DOI: 10.1016/j.cbpa.2006.06.014
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A practical view of druggability
Keller, Thomas H.; Pichota, Arkadius; Yin, Zheng
Current Opinion in Chemical Biology (2006), 10 (4), 357-361CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
A review. The introduction of Lipinski's Rule of Five has initiated a profound shift in the thinking paradigm of medicinal chemists. Understanding the difference between biol. active small mols. and drugs became a priority in the drug discovery process, and the importance of addressing pharmacokinetic properties early during lead optimization is a clear result. These concepts of drug-likeness and druggability have been extended to proteins and genes for target identification and selection. How should these concepts be integrated practically into the drug discovery process. This review summarizes the recent advances in the field and examines the usefulness of the rules of the game in practice from a medicinal chemist's standpoint.
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Lipinski, C. A. Drug Discovery Today: Technol. 2004, 1, 337– 341 DOI: 10.1016/j.ddtec.2004.11.007
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Lead- and drug-like compounds: the rule-of-five revolution
Lipinski, Christopher A.
Drug Discovery Today: Technologies (2004), 1 (4), 337-341CODEN: DDTTB5; ISSN:1740-6749. (Elsevier B.V.)
A review. Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochem. features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clin. success. Physicochem. features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compds. differ from those of drug-like compds. is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chem. tools to probe biol. space. All these topics frame the scope of this short review/perspective.
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Macarron, R. Drug Discovery Today 2006, 11, 277– 279 DOI: 10.1016/j.drudis.2006.02.001
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Critical review of the role of HTS in drug discovery
Macarron Ricardo
Drug discovery today (2006), 11 (7-8), 277-9 ISSN:1359-6446.
'A wise use of lead discovery tactics will distinguish successful drug discovery engines.'
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Koehn, F. E. MedChemComm 2012, 3, 854– 865 DOI: 10.1039/c2md00316c
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Biosynthetic medicinal chemistry of natural product drugs
Koehn, Frank E.
MedChemComm (2012), 3 (8), 854-865CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Natural products are an unsurpassed source of lead structures for drug discovery. However, these mols., many of which fall into the beyond-rule-of-5 chem. space, are often difficult to optimize by chem. means because of their complex structures. Biosynthetic engineering of the producing host organism offers an important tool for the modification of complex natural products, leading to analogs which are unattainable by chem. semisynthesis. This review describes the current role of natural products in lead generation and the principles behind biosynthetic medicinal chem. It then goes on to describe five distinct drugs - salinosporamide, geldanamycin, FK506, rapamycin, and epothilone - to exemplify how biosynthetic engineering approaches have contributed to the advancement of natural product clin. candidates.
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Doak, B. C.; Over, B.; Giordanetto, F.; Kihlberg, J. Chem. Biol. 2014, 21, 1115– 1142 DOI: 10.1016/j.chembiol.2014.08.013
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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
Doak, Bradley Croy; Over, Bjorn; Giordanetto, Fabrizio; Kihlberg, Jan
Chemistry & Biology (Oxford, United Kingdom) (2014), 21 (9), 1115-1142CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
A review. The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compds. with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clin. candidates with mol. wt. (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramol. hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.
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Camp, D.; Garavelas, A.; Campitelli, M. J. Nat. Prod. 2015, 78, 1370– 1382 DOI: 10.1021/acs.jnatprod.5b00255
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Macarron, R.; Banks, M. N.; Bojanic, D.; Burns, D. J.; Cirovic, D. A.; Garyantes, T.; Green, D. V. S.; Hertzberg, R. P.; Janzen, W. P.; Paslay, J. W.; Schopfer, U.; Sittampalam, G. S. Nat. Rev. Drug Discovery 2011, 10, 188– 195 DOI: 10.1038/nrd3368
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Impact of high-throughput screening in biomedical research
Macarron, Ricardo; Banks, Martyn N.; Bojanic, Dejan; Burns, David J.; Cirovic, Dragan A.; Garyantes, Tina; Green, Darren V. S.; Hertzberg, Robert P.; Janzen, William P.; Paslay, Jeff W.; Schopfer, Ulrich; Sittampalam, G. Sitta
Nature Reviews Drug Discovery (2011), 10 (3), 188-195CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A review. High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.
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Macarron, R. Nat. Chem. Biol. 2015, 11, 904– 905 DOI: 10.1038/nchembio.1937
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Chemical libraries How dark is HTS dark matter?
Macarron, Ricardo
Nature Chemical Biology (2015), 11 (12), 904-905CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
Selecting compds. for the chem. library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many mols. in the Novartis and NIH Mol. Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compds. of interest.
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Wassermann, A. M.; Lounkine, E.; Hoepfner, D.; Le Goff, G.; King, F. J.; Studer, C.; Peltier, J. M.; Grippo, M. L.; Prindle, V.; Tao, J.; Schuffenhauer, A.; Wallace, I. M.; Chen, S.; Krastel, P.; Cobos-Correa, A.; Parker, C. N.; Davies, J. W.; Glick, M. Nat. Chem. Biol. 2015, 11, 958– 966 DOI: 10.1038/nchembio.1936
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Dark chemical matter as a promising starting point for drug lead discovery
Wassermann Anne Mai; Lounkine Eugen; Le Goff Gaelle; King Frederick J; Peltier John M; Grippo Melissa L; Wallace Iain M; Chen Shanni; Davies John W; Glick Meir; Hoepfner Dominic; Studer Christian; Schuffenhauer Ansgar; Krastel Philipp; Cobos-Correa Amanda; Parker Christian N; King Frederick J; Prindle Vivian; Tao Jianshi
Nature chemical biology (2015), 11 (12), 958-66 ISSN:.
High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.
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Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S.-N.; Graham, J.; Pauli, G. F. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b01009
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Baell, J.; Walters, M. A. Nature 2014, 513, 481– 483 DOI: 10.1038/513481a
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Chemistry: Chemical con artists foil drug discovery
Baell, Jonathan; Walters, Michael A.
Nature (London, United Kingdom) (2014), 513 (7519), 481-483CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
A review. Naivety about promiscuous, assay-duping mols. is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters. Academic drug discoverers must be more vigilant. Mols. that show the strongest activity in screening might not be the best starting points for drugs. PAINS hits should almost always be ignored. Even trained medicinal chemists have to be careful until they become experienced in screening.
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Erlanson, D. A. J. Med. Chem. 2015, 58, 2088– 2090 DOI: 10.1021/acs.jmedchem.5b00294
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Ryan, N. J. Drugs 2014, 74, 1709– 1714 DOI: 10.1007/s40265-014-0287-4
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Ataluren: First Global Approval
Ryan, Nicola J.
Drugs (2014), 74 (14), 1709-1714CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
A review. Nonsense mutations are implicated in 5-70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren (Translarna) is an orally available, small mol. compd. that targets nonsense mutations, and is the first drug in its class. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full-length, functional proteins. This article summarizes the milestones in the development of ataluren leading to its conditional first approval for nonsense mutation DMD.
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Hoelder, S.; Clarke, P. A.; Workman, P. Mol. Oncol. 2012, 6, 155– 176 DOI: 10.1016/j.molonc.2012.02.004
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Discovery of small molecule cancer drugs: Successes, challenges and opportunities
Hoelder, Swen; Clarke, Paul A.; Workman, Paul
Molecular Oncology (2012), 6 (2), 155-176CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)
A review. The discovery and development of small mol. cancer drugs has been revolutionized over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalized medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biol. and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small mol. cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chem. hit and lead generation; lead optimization to identify a clin. drug candidate; and finally hypothesis-driven, biomarker-led clin. trials. Although all of these steps are crit., we view target validation and selection and the conduct of biol.-directed clin. trials as esp. important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clin. development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and tech. challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solns. to overcome the Valley of Death' between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalized medicine for cancer patients.
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Isolation of a new thymine pentoside from sponges
Bergmann, Werner; Feeney, Robert J.
Journal of the American Chemical Society (1950), 72 (), 2809-10CODEN: JACSAT; ISSN:0002-7863.
Extn. of certain air-dried sponges (genus Cryptatothia) in Soxhlet app. with acetone gives crystals, from the boiling solvent, of a mixt. of nucleosides not previously reported. Repeating recrystn. from H2O gives one m. 246-7°, [α]D22 + 80.0° (c, 1.1 in 8% NaOH), [α]D22 + 92° (c, 0.88 in pyridine). Calcd. for C10H14N2O6: C, 46.50; H, 5.48; N, 10.85; Found C, 46.84; H, 5.42; N, 11.09. A neutral aq. soln. absorption spectra gave one max. at 2690 A. (EM 9250). Failure to show spectral response to change in pH is similar to that of thymine desoxyriboside. Vigorous hydrolysis with boiling 10% H2SO4 gave thymine m. 321°. Isolation and identification of the carbohydrate fragment was unsuccessful. To show it is a thymine pentafuranoside, benzoylation by modified Schotten-Baumann gives a tribenzoate m. 190-1°, [α]D22 + 78.3° (c, 0.28 in MeOH), prepd. similarly the tri-p-bromobenzoate m. 223-4° and titration according to the method of Lythgoe and Todd (C.A. 39, 912.1) used 1 mole periodate without formation of formic acid. The proposed name is spongothymidine.
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Bergmann, W.; Feeney, R. J. J. Org. Chem. 1951, 16, 981– 987 DOI: 10.1021/jo01146a023
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Marine products. XXXIX. The nucleosides of sponges. III. Spongothymidine and spongouridine
Bergmann, Werner; Burke, Derek C.
Journal of Organic Chemistry (1955), 20 (), 1501-7CODEN: JOCEAH; ISSN:0022-3263.
cf. C.A. 46, 5609h; 50, 7808g. Paper chromatography of certain crude fractions of the nucleosides (I) isolated from Crypotethia crypta revealed the presence of spongothymidine (II), spongosine (III), and spongouridine (IV). These I have now been sepd. I are absorbed on a Dowex-1 resin (OH- form) and eluted with a NH4OH-NH4O2CH buffer soln. (pH 9.5) which elutes III. Further elution with a buffer of pH 8.3 gives II, thymine, uracil, and IV in the order given. IV, cubic crystals, m. 226-8°, [α]D 97° (c 0.6, 8% NaOH), 126° (c 1, H2O), pK 9.3. Heating 5 mg. IV with 2 cc. 90% HCO2H 2 hrs. at 150° and paper-chromatographing the product indicate the presence of unchanged IV and some uracil. Refluxing II 3 hrs. in 5% HCl or 5 hrs. in 10% H2SO4, or heating it in a sealed tube 2 hrs. with 10% H2SO4 at 125° or with 5% HCl-MeOH 5 hrs. at 100° leaves II unchanged. Reducing 467 mg. II in 100 cc. liquid NH8 and 5 cc. EtOH with 0.4 g. Na (cf. loc. cit.) and passing the product through Dowex (H+ form) give 400 mg. of a yellow gum (V), [α]D -51°, which by paper chromatography (BuOH-EtOH-H2O and BuOH satd. with H2O) and by ionophoresis in a borate buffer is found to contain only arabinose. When treated with phenylhydrazine V gives a phenylosazone (VI), m. 154-5°, which does not depress the m.p. of the phenylosazone (VII) from ribose. The infrared absorption spectrum of VI is identical with that of VII but differs from that of xylose. Similar reduction of 5.3 mg. IV followed by paper chromatography indicates the presence of arabinose. Periodate oxidation of adenosine, guanosine, cytidine, uridine, II, and IV (20-50 mg.) in H2O with 5 cc. 0.2808N NaIO4 shows the consumption of 1 mole iodate without the formation of HCO2H. Paper ionophoresis of II gives a migration rate of 0.50 for II and 0.68 for IV. Oxidation of 23 mg. II with 1 cc. 0.26N NaIO4 after 24 hrs. gives a soln. with [α]D 16.3°; a similar oxidation of D-glucopyranosylthymine gives a soln. with [α]D 17°; oxidation of 21 mg. IV gives a soln. with [α]D 15°, and oxidation of 25 mg. uridine a soln. with [α]D 15.2°. The results indicate that II is 3-β-D-arabofuranosylthymine and IV is 3-β-D-arabofuranosyluracil.
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Bertin, M. J.; Schwartz, S. L.; Lee, J.; Korobeynikov, A.; Dorrestein, P. C.; Gerwick, L.; Gerwick, W. H. J. Nat. Prod. 2015, 78, 493– 499 DOI: 10.1021/np5009762
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Spongosine production by a Vibrio harveyi strain associated with the sponge Tectitethya crypta
Bertin, Matthew J.; Schwartz, Sarah L.; Lee, John; Korobeynikov, Anton; Dorrestein, Pieter C.; Gerwick, Lena; Gerwick, William H.
Journal of Natural Products (2015), 78 (3), 493-499CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
Spongosine (I), deoxyspongosine, spongothymidine (Ara T), and spongouridine (Ara U) were isolated from the Caribbean sponge Tectitethya crypta and given the general name "spongonucleosides". Spongosine, a methoxyadenosine deriv., has demonstrated a diverse bioactivity profile including anti-inflammatory activity and analgesic and vasodilation properties. Investigations into unusual nucleoside prodn. by T. crypta-assocd. microorganisms using mass spectrometric techniques have identified a spongosine-producing strain of Vibrio harveyi and several structurally related compds. from multiple strains.
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Natural Products in Medicine: Transformational Outcome of Synthetic Chemistry
Szychowski, Janek; Truchon, Jean-Francois; Bennani, Youssef L.
Journal of Medicinal Chemistry (2014), 57 (22), 9292-9308CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chem. transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Mol. modeling or X-ray structures of NP/protein complexes supporting the obsd. boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chem., in structure detn., and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivs.
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Bathula, S. R.; Akondi, S. M.; Mainkar, P. S.; Chandrasekhar, S. Org. Biomol. Chem. 2015, 13, 6432– 6448 DOI: 10.1039/C5OB00403A
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Thaker, M. N.; Wright, G. D. ACS Synth. Biol. 2015, 4, 195– 206 DOI: 10.1021/sb300092n
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Opportunities for Synthetic Biology in Antibiotics: Expanding Glycopeptide Chemical Diversity
Thaker, Maulik N.; Wright, Gerard D.
ACS Synthetic Biology (2015), 4 (3), 195-206CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
A review. Synthetic biol. offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clin. use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biol. thinking and strategies can provide new mols. and expand chem. diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biol. can expand antibiotic chem. diversity to help address the growing resistance crisis.
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Stockdale, Tegan P.; Williams, Craig M.
Chemical Society Reviews (2015), 44 (21), 7737-7763CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
Numerous variations on structural motifs exist within pharmaceutical compds. that have entered the clinic. These variations have amounted over many decades based on years of drug development assocd. with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approx. 20 all carbon cage contg. pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs contg. the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurol. activity. In addn., to an extensive overview of the history and biol. assocd. with each drug, a survey of synthetic methods used to construct these entities is presented. An anal. section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.
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Yoganathan, Sabesan; Miller, Scott J.
Journal of Medicinal Chemistry (2015), 58 (5), 2367-2377CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, the authors disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. The authors have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliph. hydroxyls on vancomycin, generating three new derivs. Incorporation of lipid chains into the vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for the new derivs. against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. The authors have also performed a structure-activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.
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Novaes, L. F. T.; Avila, C. M.; Pelizzaro-Rocha, K. J.; Vendramini-Costa, D. B.; Dias, M. P.; Trivella, D. B. B.; de Carvalho, J. E.; Ferreira-Halder, C. V.; Pilli, R. A. ChemMedChem 2015, 10, 1687– 1699 DOI: 10.1002/cmdc.201500246
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Nicolaou, K. C.
Chemistry & Biology (Oxford, United Kingdom) (2014), 21 (9), 1039-1045CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
A review. Admirable as it is, the drug discovery and development process is continuously undergoing changes and adjustments in search of further improvements in efficiency, productivity, and profitability. Recent trends in academic-industrial partnerships promise to provide new opportunities for advancements of this process through transdisciplinary collaborations along the entire spectrum of activities involved in this complex process. This perspective discusses ways to promote the emerging academic paradigm of the chem.-biol.-medicine continuum as a means to advance the drug discovery and development process.
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Prous, J. R.
Drug News & Perspectives (1996), 9 (1), 19-32CODEN: DNPEED; ISSN:0214-0934. (Prous)
A review without refs. on the historical and research perspective on th 40 new products that reached their first markets in 1995, including ten breakthrough products approved for the first time (data from the Prous Science database). The drugs covered include analgesic, anesthetic, neurol., respiratory, gastrointestinal and endocrine drugs, agents affecting blood coagulation, antiinfective therapy and immunomodulators and oncolytic drugs, treatment of poisoning and drug dependency, as well as diagnostic agents.
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Graul, Ann I.
Drug News & Perspectives (1999), 12 (1), 27-43CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review with no refs. Forty-two new chem. entities and biol. drugs and four diagnostic agents reached their first markets in 1998. During the past year, Agents Affecting Blood Coagulation and Metabolic Drugs were the most active therapeutic groups in terms of new launches, with six market introductions each. There were also six new launches in the category of Antiinfective Therapy, including two in the area of AIDS Medicines. The United States was the most active market for new products, with a total of 28 new launches in 1998, constituting 67% of the total of new introductions for the year.
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Graul, Ann I.
Drug News & Perspectives (2000), 13 (1), 37-53CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review with no refs. Forty-four new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 1999. Endocrine Drugs was the most active therapeutic group in terms of new launches, with nine market introductions, and the United States was once again the most active market for new products, with a total of 23 new launches in 1999, constituting 50% of all new introductions for the year.
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Graul, A. I. Drug News Persp. 2001, 14, 12– 31
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The year's new drugs
Graul, Ann I.
Drug News & Perspectives (2001), 14 (1), 12-31CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. Forty-four new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 2000. Gastrointestinal Drugs was the most active therapeutic group in terms of new launches, with seven market introductions, and the United States was once again the most active single market for new products, with a total of 17 new launches in 2000, constituting 37% of all new introductions for the year.
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Graul, A. I. Drug News Persp. 2002, 15, 29– 43
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The Year's New Drugs
Graul Ann I.
Drug news & perspectives (2002), 15 (1), 29-43 ISSN:0214-0934.
Thirty-four new chemical entities and biological drugs and two diagnostic agents reached their first markets in 2001. Antiinfective Therapy was the most active therapeutic group in terms of new launches, with five market introductions, and the United States was the most active single market for new products, with a total of 15 new launches in 2001, constituting 43% of all new introductions for the year. (c) 2002 Prous Science. All rights reserved.
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Graul, A. I. Drug News Persp. 2003, 16, 22– 39
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The year's new drugs
Graul Ann I
Drug news & perspectives (2003), 16 (1), 22-39 ISSN:0214-0934.
The United States was the most active market for new product launches (22 products, 62.5%) in a year that saw 35 new chemical entities and biological drugs and two diagnostic agents reach their first markets. The most active therapeutic groups were anti-infective, oncolytic and metabolic drugs with five launches for each.
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Graul, A. I. Drug News Persp. 2004, 17, 43– 57
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The year's new drugs
Graul, Ann I.
Drug News & Perspectives (2004), 17 (1), 43-57CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. Inaugurated 16 yr ago, this annual article provides the opportunity to present from both a historical and a research perspective those mol. entities and biol. drugs that were launched or approved in various countries for the first time during the past year. According to our records, 30 new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 2003. Another six new products were approved for the first time in 2003 but were not launched before year-end. During the past year, Endocrine and Metabolic Drugs was the most active therapeutic group in terms of new launches, with six market introductions. The United States was again the most active market for new products, with a total of 20 new launches in 2003, constituting 66.6% of the total of new introductions for the year.
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Graul, A. I.; Prous, J. R. Drug News Persp. 2005, 18, 21– 36
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A historical and research perspective on the 23 new products that reached their first markets in 2004. The year's new drugs
Graul, Ann I.; Prous, J. R.
Drug News & Perspectives (2005), 18 (1), 21-36CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. Twenty-three new biol. drugs and diagnostic agents reached their first markets in 2004. The oncolytic drugs therapeutic group was the most active in terms of new launches, with seven market introductions, and the United States was the most active single market for new products, with a total of 10 new launches in 2004.
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Graul, A. I.; Prous, J. R. Drug News Persp. 2006, 19, 33– 53
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The year's new drugs
Graul, Ann I.; Prous, J. R.
Drug News & Perspectives (2006), 19 (1), 33-53CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. Forty-one new biol. drugs and diagnostic agents reached their first markets in 2005. Antiinfective therapy, immunomodulators and agents for immunization and central nervous system drugs were the most active therapeutic groups in terms of new chem. entities launched for the first time, with six market introductions apiece. The United States was again the most active market for new products, with a total of 21 new launches in 2005, constituting 50% of the total of new introductions for the year.
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Graul, A. I.; Sorbera, L. A.; Bozzo, J.; Serradell, N.; Revel, L.; Prous, J. R. Drug News Persp. 2007, 20, 17– 44
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The year's new drugs and biologics-2006
Graul, A. I.; Sorbera, L. A.; Bozzo, J.; Serradell, N.; Revel, L.; Prous, J. R.
Drug News & Perspectives (2007), 20 (1), 17-44CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines-this figure includes both drugs and biologies for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine-reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year's edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an anal. of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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Graul, A. I.; Prous, J. R.; Barrionuevo, M.; Bozzo, J.; Castañer, R.; Cruces, E.; Revel, L.; Rosa, E.; Serradell, N.; Sorbera, L. A. Drug News Persp. 2008, 21, 7– 35
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The year's new drugs and biologics-2007
Graul, A. I.; Prous, J. R.; Barrionuevo, M.; Bozzo, J.; Castaner, R.; Cruces, E.; Revel, L.; Rosa, E.; Serradell, N.; Sorbera, L. A.
Drug News & Perspectives (2008), 21 (1), 7-35CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2007, 30 new medicines-this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents-reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for 45% of the new medicines launched in 2007. Several new features were introduced last year, and have been maintained due to a high level of interest from readers: a deeper insight into the three first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life span of medicines; and an anal. of the market for these new medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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Graul, A. I.; Revel, L.; Barrionuevo, M.; Cruces, E.; Rosa, E.; Vergés, C.; Lupone, B.; Diaz, N.; Castañe, R. Drug News Perspect. 2009, 22, 7– 27 DOI: 10.1358/dnp.2009.22.1.1303754
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The year's new drugs & biologics - 2008
Graul, Ann I.; Revel, Laura; Barrionuevo, Meritxell; Cruces, Elisabet; Rosa, Esmeralda; Verges, Clara; Lupone, Becky; Diaz, Nuria; Castaner, Rosa
Drug News & Perspectives (2009), 22 (1), 7-29CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2008, 31 new medicines-this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents-reached their first markets. Line extensions (new indications, new formulations and new combinations of previously marketed products) accounted for more than one-third of the new medicines launched in 2008. In addn. to providing an overview of all drugs and biologies launched or approved for the first time ever in the previous year, this article will also review in further depth the first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; and a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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Graul, A. I.; Sorbera, L. A.; Pina, P.; Tell, M.; Cruces, E.; Rosa, E.; Stringer, M.; Castañer, R.; Revel, L. Drug News Perspect. 2010, 23, 7– 36 DOI: 10.1358/dnp.2010.23.1.1440373
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The year's new drugs & biologics - 2009
Graul, Ann I.; Sorbera, Lisa; Pina, Patricia; Tell, Montse; Cruses, Elisabet; Rosa, Esmeralda; Stringer, Mark; Castaner, Rosa; Revel, Laura
Drug News & Perspectives (2010), 23 (1), 7-36CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2009, 51 new medicines and vaccines reached their first markets. Line extensions (new indications, new formulations and new combinations of previously marketed products) accounted for more than 30% of the new products launched in 2009. In addn. to providing an overview of all drugs and biologics launched or approved for the first time ever in the previous year, this article will also review in further depth the first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; and a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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Graul, A. I.; Cruces, E. Drugs Today 2011, 47, 27– 51 DOI: 10.1358/dot.2011.47.1.1587820
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The year's new drugs & biologics, 2010
Graul, A. I.; Cruces, E.
Drugs of Today (2011), 47 (1), 27-51CODEN: MDACAP; ISSN:1699-3993. (Prous Science)
A review. The year 2010 marked the first launch for a no. of new drugs and biologics, including several important innovations and therapeutic advances. Twenty-nine new chem. entities and biologics for therapeutic use reached their first markets in 2010. Following a growing tendency in recent years, at least 20 important line extensions were also introduced last year. Both figures are significantly lower than those registered in 2009. Pharma and biotech companies also became leaner and more competitive in 2010 through two processes: prioritizing R&D and discontinuing less promising projects, and merging with or acquiring companies with complementary strengths and weaknesses. This review provides a brief overview of the highlights of 2010.
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Graul, A. I.; Cruces, E.; Dulsat, C.; Arias, E.; Stringer, M. Drugs Today 2012, 48, 33– 77 DOI: 10.1358/dot.2012.48.1.1769676
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The Year's new drugs & biologics, 2011
Graul, A. I.; Cruces, E.; Dulsat, C.; Arias, E.; Stringer, M.
Drugs of Today (2012), 48 (1), 33-77CODEN: MDACAP; ISSN:1699-3993. (Thomson Reuters)
A review. 2011 Was a good year in many respects for the pharmaceutical industry, esp. regarding the approval and launch of several important new products. The FDA reported a record high rate of approvals during FY2011 (Oct. 1, 2010-Sept. 30, 2011), reflecting the agency's commitment to maintaining "a state-of-the-art drug approval process that brings important drugs to market quickly and efficiently" (1). While not all of the new drugs and biologics listed in FDA's fiscal year summary meet the criteria for inclusion in this article, most of them do, and hence are reviewed in the following pages. Also covered in this year's expanded article are new approvals and new launches in other global markets, line extensions and other developments of interest to the industry: generic drug approvals, product withdrawals and discontinuations, new developments in the area of orphan drugs and diseases, and more.
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Graul, A. I.; Lupone, B.; Cruces, E.; Stringer, M. Drugs Today 2013, 49, 33– 38
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2012 in review - part I: the year's new drugs & biologics
Graul A I; Lupone B; Cruces E; Stringer M
Drugs of today (Barcelona, Spain : 1998) (2013), 49 (1), 33-68 ISSN:1699-3993.
Thirty-seven new launches are considered in the first part of this annual review article, including 36 drugs and biologics that reached their first markets worldwide in 2012 and one additional drug that was launched at the end of December 2011. In addition, 26 significant new line extensions (new indications, new formulations and new combinations of existing drugs) that were launched for the first time in 2012 are discussed in this review. Also included are new drugs and biologics and new line extensions that were approved for the first time between January and December 2012, although they were not launched before the end of the year.
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Graul, A. I.; Cruces, E.; Stringer, M. Drugs Today 2014, 50, 51– 100 DOI: 10.1358/dot.2014.50.1.2116673
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The year's new drugs & biologics, 2013: Part I
Graul A I; Cruces E; Stringer M
Drugs of today (Barcelona, Spain : 1998) (2014), 50 (1), 51-100 ISSN:1699-3993.
This article provides a comprehensive overview of the 56 new drugs and biologics introduced for the first time in 2013, the largest number in at least a decade. This includes 20 new orphan drugs and 10 first-in-class agents, as well as the first three products bearing the FDA's new Breakthrough Therapy Designation. The review also covers 30 important new line extensions, encompassing new indications, new formulations and new combinations of previously marketed agents. In addition to this bumper crop of new launches, another 19 products were approved for the first time during the year but not yet launched by the close of this article; these new products are also discussed.
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Graul, A. I.; Navarro, D.; Dulsat, G.; Cruces, E.; Tracy, M. Drugs Today 2014, 50, 133– 158 DOI: 10.1358/dot.2014.50.2.2122810
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The year's new drugs & biologics, 2013: Part II
Graul A I; Navarro D; Dulsat C; Cruces E; Tracy M
Drugs of today (Barcelona, Spain : 1998) (2014), 50 (2), 133-58 ISSN:1699-3993.
The demise of the pharmaceutical industry, so pessimistically predicted by many in recent years, has not come to pass and in fact the patient is alive and well. New programs enacted by drug regulators have been enthusiastically taken up by the industry, including the FDA's breakthrough therapy and qualified infectious disease product (QIDP) designations, as well as the now-consolidated orphan drug programs in many countries. Pharma companies pragmatically wean nonperformers from the pipeline in an efficient manner, resulting in somewhat leaner but higher-quality pipelines. Mergers and acquisitions also continue to drive consolidation and efficiency in the industry, a trend that continued during 2013. This article provides an updated review of these and other trends in the pharmaceutical industry in the year just passed.
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Graul, A. I.; Stringer, M. Drugs Today 2015, 51, 37– 87 DOI: 10.1358/dot.2015.51.1.2279964
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The year's new drugs & biologics, 2014: Part I
Graul A I; Cruces E; Stringer M
Drugs of today (Barcelona, Spain : 1998) (2015), 51 (1), 37-87 ISSN:1699-3993.
A year-end wrap-up of new drug approvals and launches reveals that activity in the pharmaceutical industry continues at a high level, with 55 new drugs and biologics introduced on their first markets in 2014 (as of December 23, 2014). Additionally, 29 important new line extensions (new formulations, new combinations or new indications for previously marketed products) also reached their first markets during the year. The most active therapeutic group in terms of new launches was anti-infective therapies, with 11 new drugs and biologics launched, most for the treatment of multidrug-resistant bacterial infections or hepatitis C. The most active market for new launches was again the U.S., site of more than half of all new launches in 2014. However new launch activity increased considerably last year in Japan, which actually pulled ahead of the E.U. for the first time in many years. In another important new development, 15 of the new drugs and biologics launched last year had orphan drug status, 5 had breakthrough therapy designation and 3 had Qualified Infectious Disease Product (QIDP) status. Another 19 products were approved for the first time during the year but not yet launched by close of this article; most are slated for launch in the first months of the new year.
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Ten things you should know about protein kinases: IUPHAR Review 14
Fabbro, Doriano; Cowan-Jacob, Sandra W.; Moebitz, Henrik
British Journal of Pharmacology (2015), 172 (11), 2675-2700CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
Many human malignancies are assocd. with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on 'the 10 things you should know about protein kinases and their inhibitors', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the '10 things' have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncol. indications.
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Fabbro, D.; Ruetz, S.; Buchdunger, E.; Cowan-Jacob, S. W.; Fendrich, G.; Liebtanz, J.; Mestan, J.; O’Reilly, T.; Traxler, P.; Chaudhuri, B.; Fretz, H.; Zimmermann, J.; Meyer, T.; Caravatti, G.; Furet, P.; Manley, P. W. Pharmacol. Ther. 2002, 93, 79– 98 DOI: 10.1016/S0163-7258(02)00179-1
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Pharmacology & Therapeutics (2002), 93 (2-3), 79-98CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science Inc.)
A review. Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biol. processes, such as control of cell growth, metab., differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-mol. wt. therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clin. trials). Three examples of inhibitors of protein kinases are reviewed, including low-mol. wt. compds. targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrrolopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec, Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear assocn. with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clin. utility of protein kinase inhibitors as therapeutic agents. In a preclin. model, STI571 (Glivec, Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematol. and cytogenetic responses in CML and clin. responses in the c-Kit-driven gastrointestinal tumors.
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Tiligada, E.; Ishii, M.; Riccardi, C.; Spedding, M.; Simon, H.-U.; Teixeira, M. M.; Cuervo, M. L. C.; Holgate, S. T.; Levi-Schaffer, F. Br. J. Pharmacol. 2015, 172, 4217– 4227 DOI: 10.1111/bph.13219
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The expanding role of immunopharmacology - IUPHAR Review 16
Tiligada, Ekaterini; Ishii, Masaru; Riccardi, Carlo; Spedding, Michael; Simon, Hans-Uwe; Teixeira, Mauro Martins; Landys Chovel Cuervo, Mario; Holgate, Stephen T.; Levi-Schaffer, Francesca
British Journal of Pharmacology (2015), 172 (17), 4217-4227CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacol. research have made available new classes of clin. relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a no. of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacol. is presently considered as one of the expanding fields of pharmacol. Immunopharmacol. addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clin. needs. While in the near future a no. of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunol., pharmacol. and drug discovery. The newly formed ImmuPhar () is the Immunopharmacol. Section of the International Union of Basic and Clin. Pharmacol. (IUPHAR, ). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiol. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.
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Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin
Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.; Cohen, N-C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G.
Chemistry & Biology (2000), 7 (7), 493-504CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)
Background: The aspartic proteinase renin plays an important physiol. role in the regulation of blood pressure. It catalyzes the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compds. has made it to the end of clin. trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. Results: Crystal structure anal. of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chem. optimization process. Structure anal. revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addn., however, these compds. interact with a hitherto unrecognized large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to the S3sp sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3sp were optimized. Conclusions: Our design approach led to compds. with high in vitro affinity and specificity for renin, favorable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
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Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; Cohen, N.-C.; Rasetti, V.; Ruger, H.; Goschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.; Herold, P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A.; Bedigian, M. P. Biochem. Biophys. Res. Commun. 2003, 308, 698– 705 DOI: 10.1016/S0006-291X(03)01451-7
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Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site
Politi, Aggeliki; Leonis, Georgios; Tzoupis, Haralambos; Ntountaniotis, Dimitrios; Papadopoulos, Manthos G.; Grdadolnik, Simona Golic; Mavromoustakos, Thomas
Molecular Informatics (2011), 30 (11-12), 973-985CODEN: MIONBS; ISSN:1868-1743. (Wiley-VCH Verlag GmbH & Co. KGaA)
Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational anal. were explored using 1D and 2D NMR spectroscopy, as well as random search and mol. dynamics (MD) simulations. For the first time, MD calcns. have also been performed for aliskiren at the receptor site, in order to reveal its mol. basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that dets. the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Addnl. mol. mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calcns. for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.
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Tzoupis, H.; Leonis, G.; Megariotis, G.; Supuran, C. T.; Mavromoustakos, T.; Papadopoulos, M. G. J. Med. Chem. 2012, 55, 5784– 5796 DOI: 10.1021/jm300180r
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Palomo, J. M. RSC Adv. 2014, 4, 32658– 32672 DOI: 10.1039/C4RA02458C
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Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides
Palomo, Jose M.
RSC Advances (2014), 4 (62), 32658-32672CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A review. This review article highlights the strategies to successfully perform an efficient solid-phase synthesis of complex peptides including posttranslational modifications, fluorescent labels, and reporters or linking groups of exceptional value for biol. studies of several important diseases. The solid-phase approach is the best alternative to synthesize these peptides rapidly and in high amts. The key aspects that need to be considered when performing a peptide synthesis in solid phase of these mols. are discussed.
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Natural-product-derived fragments for fragment-based ligand discovery
Over, Bjoern; Wetzel, Stefan; Gruetter, Christian; Nakai, Yasushi; Renner, Steffen; Rauh, Daniel; Waldmann, Herbert
Nature Chemistry (2013), 5 (1), 21-28CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
Fragment-based ligand and drug discovery predominantly employs sp2-rich compds. covering well-explored regions of chem. space. Despite the ease with which such fragments can be coupled, this focus on flat compds. is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biol. validated natural products are rich in stereogenic centers and populate areas of chem. space not occupied by av. synthetic mols. Here, we have analyzed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centers. The structures of the cluster centers differ from previously explored fragment libraries, but for nearly half of the clusters representative members are com. available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallog. and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.
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Bauer, A.; Bronstrup, M. Nat. Prod. Rep. 2014, 31, 35– 60 DOI: 10.1039/C3NP70058E
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Industrial natural product chemistry for drug discovery and development
Bauer, Armin; Broenstrup, Mark
Natural Product Reports (2014), 31 (1), 35-60CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. In addn. to their prominent role in basic biol. and chem. research, natural products are a rich source of com. products for the pharmaceutical and other industries. Industrial natural product chem. is of fundamental importance for successful product development, as the vast majority (ca. 80%) of com. drugs derived from natural products require synthetic efforts, either to enable economical access to bulk material, and/or to optimize drug properties through structural modifications. This review aims to illustrate issues on the pathway from lead to product, and how they have been successfully addressed by modern natural product chem. It is focused on natural products of current relevance that are, or are intended to be, used as pharmaceuticals.
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Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Nat. Prod. Rep. 2014, 31, 419– 432 DOI: 10.1039/C3NP70090A
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Natural product synthesis in the age of scalability
Kuttruff, Christian A.; Eastgate, Martin D.; Baran, Phil S.
Natural Product Reports (2014), 31 (4), 419-432CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. The ability to procure useful quantities of a mol. by simple, scalable routes is emerging as an important goal in natural product synthesis. Approaches to mols. that yield substantial material enable collaborative investigations (such as SAR studies or eventual com. prodn.) and inherently spur innovation in chem. As such, when evaluating a natural product synthesis, scalability is becoming an increasingly important factor. This highlight discussed recent examples of natural product synthesis from the authors' lab. and others, where the prepn. of gram-scale quantities of a target compd. or a key intermediate allowed for a deeper understanding of biol. activities or enabled further investigational collaborations.
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Liu, Y.-Y.; Wang, Y.; Walsh, T. R.; Yi, L.-X.; Zhang, R.; Spencer, J.; Doi, Y.; Tian, G.; Dong, B.; Huang, X.; Yu, L.-F.; Gu, D.; Ren, H.; Chen, X.; Lv, L.; He, D.; Zhou, H.; Liang, Z.; Liu, J.-H.; Shen, J. Lancet Infect. Dis. 2015, DOI: 10.1016/S1473-3099(15)00424-7
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Kohno, J.; Kawahata, T.; Otake, T.; Morimoto, M.; Mori, H.; Ueba, N.; Nishio, M.; Kinumaki, A.; Komatsubara, S.; Kawashima, K. Biosci., Biotechnol., Biochem. 1996, 60, 1036– 1037 DOI: 10.1271/bbb.60.1036
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Camp, D. Drugs Future 2013, 38, 245– 256 DOI: 10.1358/dof.2013.038.04.1940442
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Homoharringtonine/Omacetaxine Mepesuccinate: The Long and Winding Road to Food and Drug Administration Approval
Kantarjian, Hagop M.; O'Brien, Susan; Cortes, Jorge
Clinical Lymphoma, Myeloma & Leukemia (2013), 13 (5), 530-533CODEN: CLMLCQ; ISSN:2152-2669. (Elsevier)
A review. Homoharringtonine/omacetaxine is a unique agent with a long history of research development. It has been recently approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia after failure of 2 or more tyrosine kinase inhibitors. Research with this agent has spanned over 40 years, with many instructive lessons to cancer research, which are summarized in this review.
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Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396– 407 DOI: 10.1038/nchembio.2007.1
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Modern synthetic efforts toward biologically active terpenes
Maimone, Thomas J.; Baran, Phil S.
Nature Chemical Biology (2007), 3 (7), 396-407CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
A review with refs. Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral, carbocyclic skeletons. Further oxidn. and rearrangement results in an almost endless no. of conceivable structures. The enormous structural diversity presented by this class of natural products ensures a broad range of biol. properties-ranging from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on synthetic strategies directed toward some of the most complex, biol. relevant terpenes prepd. by total synthesis within the past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct such natural products and the key chem. transformations and strategies that have been developed to meet these challenges.
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McKerrall, S. J.; Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5799– 5810 DOI: 10.1021/ja501881p
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Development of a Concise Synthesis of (-)-Ingenol
McKerrall, Steven J.; Joergensen, Lars; Kuttruff, Christian A.; Ungeheuer, Felix; Baran, Phil S.
Journal of the American Chemical Society (2014), 136 (15), 5799-5810CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The complex diterpenoid (-)-ingenol (I) possesses a uniquely challenging scaffold and constitutes the core of a recently approved anti-cancer drug. This full account details the development of a short synthesis of I that takes place in two sep. phases (cyclase and oxidase) as loosely modeled after terpene biosynthesis. Initial model studies establishing the viability of a Pauson-Khand approach to building up the carbon framework are recounted. Extensive studies that led to the development of a 7-step cyclase phase to transform (+)-3-carene into a suitable tigliane-type core are also presented. A variety of competitive pinacol rearrangements and cyclization reactions were overcome to develop a 7-step oxidase phase producing (-)-ingenol. The pivotal pinacol rearrangement is further examd. through DFT calcns., and implications for the biosynthesis of (-)-ingenol are discussed.
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Michaudel, Q.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2015, 48, 712– 721 DOI: 10.1021/ar500424a
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Shah, S.; Ryan, C. J. Drugs Future 2009, 34, 873– 880 DOI: 10.1358/dof.2009.034.11.1441113
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Abiraterone acetate: CYP17 inhibitor oncolytic
Shah, S.; Ryan, C. J.
Drugs of the Future (2009), 34 (11), 873-880CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
A review. Androgen deprivation therapy has been the std. of care in advanced prostate cancer for over 50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone. The term castration-resistant prostate cancer (CRPC), however, is a misnomer, as the disease is still dependent on continued activation of the androgen receptor(AR). New secondary hormonal therapies seek to prolong suppression of the AR and thus delay the development of truly hormone-"refractory" prostate cancer. Extra-gonadal androgens, and specifically adrenal androgens, represent a means for continued AR-mediated growth in CRPC and have thus become a therapeutic target. Abiraterone acetate (CB-7630) is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from phase I and II trials suggest that prostate-specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large phase III clin. trials are currently open to accrual, and if abiraterone acetate is proven to be efficacious, it will result in widespread use of a drug specifically developed to suppress adrenal androgens.
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Doronina, S. O.; Mendelsohn, B. A.; Bovee, T. D.; Cerveny, C. G.; Alley, S. C.; Meyer, D. L.; Oflazoglu, E.; Toki, B. E.; Sanderson, R. J.; Zabinski, R. F.; Wahl, A. F.; Senter, P. D. Bioconjugate Chem. 2006, 17, 114– 124 DOI: 10.1021/bc0502917
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Enhanced Activity of Monomethylauristatin F through Monoclonal Antibody Delivery: Effects of Linker Technology on Efficacy and Toxicity
Doronina, Svetlana O.; Mendelsohn, Brian A.; Bovee, Tim D.; Cerveny, Charles G.; Alley, Stephen C.; Meyer, Damon L.; Oflazoglu, Ezogelin; Toki, Brian E.; Sanderson, Russell J.; Zabinski, Roger F.; Wahl, Alan F.; Senter, Peter D.
Bioconjugate Chemistry (2006), 17 (1), 114-124CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
We have previously shown that antibody-drug conjugates (ADCs) consisting of cAC10 (anti-CD30) linked to the antimitotic agent monomethylauristatin E (MMAE) lead to potent in vitro and in vivo activities against antigen pos. tumor models. MMAF is a new antimitotic auristatin deriv. with a charged C-terminal phenylalanine residue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE, most likely due to impaired intracellular access. In vitro cytotoxicity studies indicated that mAb-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-MMAF (mAb-L1-MMAF) conjugates were >2200-fold more potent than free MMAF on a large panel of CD30 pos. hematol. cell lines. As with cAC10-L1-MMAE, the corresponding MMAF ADC induced cures and regressions of established xenograft tumors at well tolerated doses. To further optimize the ADC, several new linkers were generated in which various components within the L1 linker were either altered or deleted. One of the most promising linkers contained a noncleavable maleimidocaproyl (L4) spacer between the drug and the mAb. CAC10-L4-MMAF was approx. as potent in vitro as cAC10-L1-MMAF against a large panel of cell lines and was equally potent in vivo. Importantly, cAC10-L4-MMAF was tolerated at >3 times the MTD of cAC10-L1-MMAF. LCMS studies indicated that drug released from cAC10-L4-MMAF was the cysteine-L4-MMAF adduct, which likely arises from mAb degrdn. within the lysosomes of target cells. This new linker technol. appears to be ideally suited for drugs that are both relatively cell-impermeable and tolerant of substitution with amino acids. Thus, alterations of the linker have pronounced impacts on toxicity and lead to new ADCs with greatly improved therapeutic indexes.
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Smaglo, B. G.; Aldeghaither, D.; Weiner, L. M. Nat. Rev. Clin. Oncol. 2014, 11, 637– 648 DOI: 10.1038/nrclinonc.2014.159
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The development of immunoconjugates for targeted cancer therapy
Smaglo, Brandon G.; Aldeghaither, Dalal; Weiner, Louis M.
Nature Reviews Clinical Oncology (2014), 11 (11), 637-648CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)
A review. Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three sep. components: an antibody that binds to a cancer cell antigen with high specificity, an effector mol. that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not sep. from the antibody during transit and will reliably release the effector to the cancer cell or tumor stroma. The high affinity antibody-antigen interaction allows specific and selective delivery of a range of effectors, including pharmacol. agents, radioisotopes, and toxins, to cancer cells. Some anticancer mols. are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.
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Tzogani, K.; Straube, M.; Hoppe, U.; Kiely, P.; O’Dea, G.; Enzmann, H.; Salmon, P.; Salmonson, T.; Pignatti, F. J. Dermatol. Treat. 2014, 25, 371– 374 DOI: 10.3109/09546634.2013.789474
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The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use
Tzogani, Kyriaki; Straube, Myrjam; Hoppe, Ute; Kiely, Peter; O'Dea, Geraldine; Enzmann, Harald; Salmon, Patrick; Salmonson, Tomas; Pignatti, Francesco
Journal of Dermatological Treatment (2014), 25 (5), 371-374CODEN: JDTREY; ISSN:0954-6634. (Informa Healthcare)
A review. The European Commission has recently issued a marketing authorisation valid throughout the European Union for 5-aminolaevulinic acid (Ameluz). The decision was based on the favorable opinion of the CHMP recommending a marketing authorization for 5-aminolaevulinic acid for treatment of actinic keratosis of mild to moderate intensity on the face and scalp. The active substance is a sensitizer used in photodynamic/radiation therapy (ATC code L01XD04). The gel should cover the lesions and approx. 5 mm of the surrounding area with a film of about 1 mm thickness. The entire treatment area should be illuminated with a red light source, either with a narrow spectrum around 630 nm and a light dose of approx. 37 J/cm2 or a broader and continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and 200 J/cm2. One session of photodynamic therapy should be administered for single or multiple lesions. Non- or partially responding lesions should be retreated in a second session 3 mo after the first treatment. 5-Aminolaevulinic acid is metabolized to protoporphyrin IX, a photoactive compd. which accumulates intracellularly in the treated actinic keratosis lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed which causes damage of cellular components and eventually destroys the target cells. The benefit with 5-aminolaevulinic acid is its ability to improve the complete response rate of actinic keratosis lesions. The most common side effects are reactions at the site of application. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the EMA website ().
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Teicher, B. A.; Tomaszewski, J. E. Biochem. Pharmacol. 2015, 96, 1– 9 DOI: 10.1016/j.bcp.2015.04.008
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Kim, K. B.; Crews, C. M. Nat. Prod. Rep. 2013, 30, 600– 604 DOI: 10.1039/c3np20126k
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137
From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes
Kim, Kyung Bo; Crews, Craig M.
Natural Product Reports (2013), 30 (5), 600-604CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. Covering: 1992 to 2012The initial enthusiasm following the discovery of a pharmacol. active natural product is often fleeting due to the poor prospects for its ultimate clin. application. Despite this, the ever-changing landscape of modern biol. has a const. need for mol. probes that can aid in our understanding of biol. processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin's pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compd. of carfilzomib (Kyprolis®), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.
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138
Kuemler, I.; Mortensen, C. E.; Nielsen, D. L. Drugs Future 2011, 36, 825– 832 DOI: 10.1358/dof.2011.036.11.1711891
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138
Trastuzumab emtansine: tumor-activated prodrug (TAP) immunoconjugate oncolytic
Kuemler, I.; Mortensen, C. Ehlers; Nielsen, D. L.
Drugs of the Future (2011), 36 (11), 825-832CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
A review. Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate. The conjugate is comprised of the antibody trastuzumab, which is directed against the receptor tyrosine-protein kinase erbB-2 (HER2), a deriv. of the cytostatic agent maytansinoid DM1 (mertansine), and a linker that covalently binds these components together. Preclinically, trastuzumab emtansine has shown significant antitumor activity in HER2-pos. breast cancer cell lines and xenografts, including those resistant to trastuzumab or lapatinib. The pharmacokinetic profile is predictable, with minimal systemic exposure to free DM1. Phase I and II studies have demonstrated manageable toxicity. Phase II studies of trastuzumab emtansine monotherapy have shown response rates of 25-35% in patients with metastatic breast cancer who had previously received trastuzumab. Several combination regimens are under investigation. Phase III studies will help to define the role of trastuzumab emtansine within current treatment strategies.
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Ansell, S. M. Expert Opin. Invest. Drugs 2011, 20, 99– 105 DOI: 10.1517/13543784.2011.542147
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140
Péan, E.; Flores, B.; Hudson, I.; Sjöberg, J.; Dunder, K.; Salmonson, T.; Gisselbrecht, C.; Laane, E.; Pignatti, F. Oncologist 2013, 18, 625– 633 DOI: 10.1634/theoncologist.2013-0020
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141
Yano, S.; Kazuno, H.; Sato, T.; Suzuki, N.; Emura, T.; Wierzba, K.; Yamashita, J.; Tada, Y.; Yamada, Y.; Fukushima, M.; Asao, T. Bioorg. Med. Chem. 2004, 12, 3443– 3450 DOI: 10.1016/j.bmc.2004.04.046
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142
Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.; Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li, S. Y.; Chen, X. H.; Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.; Justice, R.; Farrell, A. T.; Pazdur, R. Clin. Cancer Res. 2015, 21, 2666– 2670 DOI: 10.1158/1078-0432.CCR-14-3119
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142
FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma
Lee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.; Ricci, M. Stacey; Saber, Haleh; Habtemariam, Bahru A.; Bullock, Julie; Bloomquist, Erik; Shen, Yuan Li; Chen, Xiao-Hong; Brown, Janice; Mehrotra, Nitin; Dorff, Sarah; Charlab, Rosane; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, Richard
Clinical Cancer Research (2015), 21 (12), 2666-2670CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered i.v. at a dose of 1000 mg/m2 over 30 min once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiol. readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathol. Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), resp. The median duration of response, the key secondary efficacy endpoint, was 8.4 mo (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. Clin Cancer Res; 21(12); 2666-70. ©2015 AACR.
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Thorkildsen, C.; Neve, S.; Larsen, B. J.; Meier, E.; Petersen, J. S. J. Pharmacol. Exp. Ther. 2003, 307, 490– 496 DOI: 10.1124/jpet.103.051987
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143
Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice
Thorkildsen, Christian; Neve, Soren; Larsen, Bjarne Due; Meier, Eddi; Petersen, Jorgen Soberg
Journal of Pharmacology and Experimental Therapeutics (2003), 307 (2), 490-496CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated Hb (HbA1C) from 8.4±0.4% (vehicle) to a min. of 6.2±0.3% (100 nmol/kg b.i.d.; p < 0.05 vs. vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was assocd. with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves β-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.
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Wang, Y.; Serradell, N.; Rosa, E.; Castaner, R. Drugs Future 2008, 33, 473– 477 DOI: 10.1358/dof.2008.033.06.1215244
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144
BI-1356: Dipeptidyl-peptidase IV inhibitor antidiabetic agent
Wang, Y.
Drugs of the Future (2008), 33 (6), 473-477CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
A review. BI-1356 is a dipeptidyl-peptidase IV (DPP IV, or CD26) inhibitor developed at Boehringer Ingelheim for the treatment of type 2 diabetes. BI-1356 demonstrated long-lasting DPP IV inhibition both in vitro and in vivo. In vitro, BI-1356 was at least 10,000-fold more selective for DPP IV than for DPP-8 and DPP-9. High potency and long-lasting inhibitory effects were also obsd. in vivo in mice and rats, the inhibition induced by BI-1356 being longer lasting than that induced by any other DPP IV inhibitor tested. BI-1356 exhibited nonlinear pharmacokinetics in healthy volunteers and patients with type 2 diabetes. Oral BI-1356 administered once daily proved to be well tolerated in healthy volunteers and patients with type 2 diabetes. Treatment with BI-1356 increased concns. of GLP-1 and reduced concns. of glucose in patients with type 2 diabetes, and it also significantly reduced Hb1Ac in diabetic patients. Phase III clin. trials are under way.
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Yoshida, T.; Akahoshi, F.; Sakashita, H.; Kitajima, H.; Nakamura, M.; Sonda, S.; Takeuchi, M.; Tanaka, Y.; Ueda, N.; Sekiguchi, S.; Ishige, T.; Shima, K.; Nabeno, M.; Abe, Y.; Anabuki, J.; Soejima, A.; Yoshida, K.; Takashina, Y.; Ishii, S.; Kiuchi, S.; Fukuda, S.; Tsutsumiuchi, R.; Kosaka, K.; Murozono, T.; Nakamaru, Y.; Utsumi, H.; Masutomi, N.; Kishida, H.; Miyaguchi, I.; Hayashi, Y. Bioorg. Med. Chem. 2012, 20, 5705– 5719 DOI: 10.1016/j.bmc.2012.08.012
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146
Kato, N.; Oka, M.; Murase, T.; Yoshida, M.; Sakairi, M.; Yamashita, S.; Yasuda, Y.; Yoshikawa, A.; Hayashi, Y.; Makino, M.; Takeda, M.; Mirensha, Y.; Kakigami, T. Bioorg. Med. Chem. 2011, 19, 7221– 7227 DOI: 10.1016/j.bmc.2011.09.043
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147
Cole, P.; Vicente, M.; Castañer, R. Drugs Future 2008, 33, 745– 751 DOI: 10.1358/dof.2008.033.09.1251351
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147
Dapagliflozin: SGLT2 inhibitor antidiabetic agent
Cole, P.; Vicente, M.; Castaner, R.
Drugs of the Future (2008), 33 (9), 745-751CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
A review. Diabetes is a growing epidemic for which new treatments are needed as it is often not controlled with current therapies. One potential means of treating diabetes is via modulation of glucose uptake. A novel strategy for achieving this is through inhibition of sodium-dependent glucose transporters (SGLTs), which mediate the process by which plasma glucose filtered in the kidney glomerulus is reabsorbed. The great majority of this process of reabsorption is mediated by SGLT2 and SGLT2 inhibitors have therefore been sought and identified in order to prevent renal glucose reabsorption and increase glucose excretion in urine. The compd. that has advanced the furthest is dapagliflozin, which demonstrated superior metabolic stability compared to early agents. Dapagliflozin also exhibited potent inhibition of SGLT2 and selectivity over SGLT1 in vitro, and was assocd. with reduced plasma glucose levels in animal models of diabetes after acute and chronic dosing. Dapagliflozin has proven safe and well tolerated in humans, with pharmacokinetic and pharmacodynamic variables indicating that daily dosing is appropriate. Double-blind trials in patients with type 2 diabetes revealed redns. in fasting and postprandial glucose, as well as significant redns. in HbA1c. Dapagliflozin has entered phase III evaluation.
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148
Chao, E. C. Drugs Future 2011, 36, 351– 357 DOI: 10.1358/dof.2011.036.05.1590789
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148
Sodium/glucose cotransporter 2 inhibitor treatment of type 2 diabetes treatment of obesity
Chao, Edward C.
Drugs of the Future (2011), 36 (5), 351-357CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
A review. Sodium/glucose cotransporters (SGLTs) serve a crit. role in the reclamation of glucose in the kidney. Blocking this reabsorption, and thus increasing the amt. of glucose excretion, has been proposed as a novel strategy for treating diabetes. Canagliflozin is a C-glucoside with a thiophene ring that acts as a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although further data from multiple ongoing phase III clin. trials of canagliflozin and other SGLT2 inhibitors are forthcoming, results to date suggest that the benefits of SGLT2 inhibition may be achieved without causing significant adverse effects. This review will provide a description of the role of the kidney in glucose homeostasis and summarize the preclin. and clin. studies published thus far on canagliflozin.
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149
White, J. R., Jr. Ann. Pharmacother. 2015, 49, 582– 598 DOI: 10.1177/1060028015573564
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150
Imamura, M.; Nakanishi, K.; Suzuki, T.; Ikegai, K.; Shiraki, R.; Ogiyama, T.; Murakami, T.; Kurosaki, E.; Noda, A.; Kobayashi, Y.; Yokota, M.; Koide, T.; Kosakai, K.; Ohkura, Y.; Takeuchi, M.; Tomiyama, H.; Ohta, M. Bioorg. Med. Chem. 2012, 20, 3263– 3279 DOI: 10.1016/j.bmc.2012.03.051
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150
Discovery of Ipragliflozin (ASP1941): A novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus
Imamura, Masakazu; Nakanishi, Keita; Suzuki, Takayuki; Ikegai, Kazuhiro; Shiraki, Ryota; Ogiyama, Takashi; Murakami, Takeshi; Kurosaki, Eiji; Noda, Atsushi; Kobayashi, Yoshinori; Yokota, Masayuki; Koide, Tomokazu; Kosakai, Kazuhiro; Ohkura, Yasufumi; Takeuchi, Makoto; Tomiyama, Hiroshi; Ohta, Mitsuaki
Bioorganic & Medicinal Chemistry (2012), 20 (10), 3263-3279CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
A series of C-glucosides with various heteroaroms. has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compds., the benzothiophene deriv. I (R =H) was found to have potent inhibitory activity against SGLT2 and good selectivity vs. SGLT1. Through further optimization of 14a, a novel benzothiophene deriv. I (R = F) (ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-Ay mice and STZ rats.
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151
Tiwari, A. Drugs Future 2012, 37, 637– 643 DOI: 10.1358/dof.2012.037.09.1848191
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151
Luseogliflozin: SGLT2 inhibitor treatment of diabetes
Tiwari, A.
Drugs of the Future (2012), 37 (9), 637-643CODEN: DRFUD4; ISSN:0377-8282. (Thomson Reuters)
A review. Luseogliflozin (TS-071), developed by Taisho Pharmaceutical, is a novel, potent sodium/glucose cotransporter 2 (SGLT2) inhibitor for the potential treatment of type 2 diabetes (T2D) and type 1 diabetes (T1D). Luseogliflozin exhibits high selectivity for SGLT2 over SGLT1 and the glucose transporters GLUT2 and GLUT4, with favorable pharmacokinetic and pharmacodynamic properties. Luseogliflozin exhibited increased urinary glucose excretion, with improved glucose tolerance and a significant redn. in fasting plasma glucose arid postprandial plasma glucose, with body wt. loss after chronic treatment in different animal models of diabetes and without an increase in plasma insulin. Clin. data in Japanese patients demonstrated that luseogliflozin was orally bioavailable, with a prolonged half-life, suitability for once-daily dosing and effective in significantly reducing glycated Hb and fasting plasma glucose, with body wt. loss. Luseogliflozin was well tolerated, without the risk of hypoglycemia and clin. meaningful changes in urinary vol., electrolyte excretion and renal function. The results from phase III clin. trials in T2D and T1D patients will be pivotal; however, the available data suggest that luseogliflozin has potential for success in this niche market segment.
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152
Poole, R. M.; Prossler, J. E. Drugs 2014, 74, 939– 944 DOI: 10.1007/s40265-014-0229-1
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153
Wilson, M. C.; Mori, T.; Rückert, C.; Uria, A. R.; Helf, M. J.; Takada, K.; Gernert, C.; Steffens, U. A. E.; Heycke, N.; Schmitt, S.; Rinke, C.; Helfrich, E. J. N.; Brachmann, A. O.; Gurgui, C.; Wakimoto, T.; Kracht, M.; Crüsemann, M.; Hentschel, U.; Abe, I.; Matsunaga, S.; Kalinowski, J.; Takeyama, H.; Piel, J. Nature 2014, 506, 58– 62 DOI: 10.1038/nature12959
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153
An environmental bacterial taxon with a large and distinct metabolic repertoire
Wilson, Micheal C.; Mori, Tetsushi; Rueckert, Christian; Uria, Agustinus R.; Helf, Maximilian J.; Takada, Kentaro; Gernert, Christine; Steffens, Ursula A. E.; Heycke, Nina; Schmitt, Susanne; Rinke, Christian; Helfrich, Eric J. N.; Brachmann, Alexander O.; Gurgui, Cristian; Wakimoto, Toshiyuki; Kracht, Matthias; Cruesemann, Max; Hentschel, Ute; Abe, Ikuro; Matsunaga, Shigeki; Kalinowski, Joern; Takeyama, Haruko; Piel, Joern
Nature (London, United Kingdom) (2014), 506 (7486), 58-62CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Cultivated bacteria such as Actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa contg. talented bacteria indeed exist. Here, the authors report the single-cell- and metagenomics-based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chem. and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chem. uniqueness of 'Entotheonella' compds. provide significant opportunities for ecol. studies and drug discovery.
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Schofield, M. M.; Jain, S.; Porat, D.; Dick, G. J.; Sherman, D. H. Environ. Microbiol. 2015, 17, 3964– 3975 DOI: 10.1111/1462-2920.12908
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154
Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743
Schofield, Michael M.; Jain, Sunit; Porat, Daphne; Dick, Gregory J.; Sherman, David H.
Environmental Microbiology (2015), 17 (10), 3964-3975CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
Ecteinascidin 743 (ET-743, Yondelis) is a clin. approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anticancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the lab. using std. techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Anal. of the ∼631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome redn. Phylogenetic anal. suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 prodn. and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster's architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. Taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically important microorganism and highlight the wide diversity of bacteria capable of making potent natural products.
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Kusari, S.; Lamshöft, M.; Kusari, P.; Gottfried, S.; Zühlke, S.; Louven, K.; Hentschel, U.; Kayser, O.; Spiteller, M. J. Nat. Prod. 2014, 77, 2577– 2584 DOI: 10.1021/np500219a
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155
Endophytes Are Hidden Producers of Maytansine in Putterlickia Roots
Kusari, Souvik; Lamshoeft, Marc; Kusari, Parijat; Gottfried, Sebastian; Zuehlke, Sebastian; Louven, Kathrin; Hentschel, Ute; Kayser, Oliver; Spiteller, Michael
Journal of Natural Products (2014), 77 (12), 2577-2584CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
Several recent studies have lent evidence to the fact that certain so-called plant metabolites are actually biosynthesized by assocd. microorganisms. In this work, we show that the original source organism(s) responsible for the biosynthesis of the important anticancer and cytotoxic compd. maytansine is the endophytic bacterial community harbored specifically within the roots of Putterlickia verrucosa and P. retrospinosa plants. Evaluation of the root endophytic community by chem. characterization of their fermn. products using HPLC-HRMSn, along with a selective microbiol. assay using the maytansine-sensitive type strain Hamigera avellanea revealed the endophytic prodn. of maytansine. This was further confirmed by the presence of AHBA synthase genes in the root endophytic communities. Finally, MALDI-imaging-HRMS was used to demonstrate that maytansine produced by the endophytes is typically accumulated mainly in the root cortex of both plants. Our study, thus, reveals that maytansine is actually a biosynthetic product of root-assocd. endophytic microorganisms. The knowledge gained from this study provides fundamental insights on the biosynthesis of so-called plant metabolites by endophytes residing in distinct ecol. niches.
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Kusari, P.; Kusari, S.; Spiteller, M.; Kayser, O. Appl. Microbiol. Biotechnol. 2015, 99, 5383– 5390 DOI: 10.1007/s00253-015-6660-8
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157
El-Elimat, T.; Raja, H. A.; Graf, T. N.; Faeth, S. H.; Cech, N. B.; Oberlies, N. H. J. Nat. Prod. 2014, 77, 193– 199 DOI: 10.1021/np400955q
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158
Wang, W.-X.; Kusari, S.; Sezgin, S.; Lamshöft, M.; Kusari, P.; Kayser, O.; Spiteller, M. Appl. Microbiol. Biotechnol. 2015, 99, 7651– 7662 DOI: 10.1007/s00253-015-6653-7
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159
Luo, Y.; Enghiad, B.; Zhao, H. Nat. Prod. Rep. 2016, DOI: 10.1039/C5NP00085H
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160
Mohimani, H.; Pevzner, P. A. Nat. Prod. Rep. 2016, 33, 73– 86 DOI: 10.1039/C5NP00050E
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160
Dereplication, sequencing and identification of peptidic natural products: from genome mining to peptidogenomics to spectral networks
Mohimani, Hosein; Pevzner, Pavel A.
Natural Product Reports (2016), 33 (1), 73-86CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
Covering: 2000 to 2015While recent breakthroughs in the discovery of peptide antibiotics and other Peptidic Natural Products (PNPs) raise a challenge for developing new algorithms for their analyses, the computational technologies for high-throughput PNP discovery are still lacking. We discuss the computational bottlenecks in analyzing PNPs and review recent advances in genome mining, peptidogenomics, and spectral networks that are now enabling the discovery of new PNPs via mass spectrometry. We further describe the connections between these advances and the new generation of software tools for PNP dereplication, de novo sequencing, and identification.
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Winn, M.; Fyans, J. K.; Zhuo, Y.; Micklefield, J. Nat. Prod. Rep. 2016, DOI: 10.1039/C5NP00099H
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The 2015 Nobel Prize in Physiol. or Medicine recognized the advances made in treating neglected tropical diseases, using drugs whose origins lie in natural products.
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Journal of Natural Products

Cite this: J. Nat. Prod. 2016, 79, 3, 629–661

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Abstract
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Figure 1
Figure 1. All new approved drugs 1981–2014; n = 1562.
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Figure 2
Figure 2. All new approved drugs by source/year.
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Figure 3
Figure 3. All small-molecule approved drugs 1981–2014s; n = 1211.
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Figure 4
Figure 4. All small-molecule approved drugs by source/year.
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Figure 5
Figure 5. Total small molecules/year.
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Figure 6
Figure 6. N, NB, ND, and S* categories by year, 1981–2014.
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Figure 7
Figure 7. Percentage of N* by year, 1981–2014.
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Scheme 1
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Figure 8
Figure 8. All anticancer drugs 1981–2014; n = 174.
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Figure 9
Figure 9. Small-molecule anticancer drugs 1940s–2014; n = 136.
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Figure 10
Figure 10. All anticancer drugs 1940s–2014 by source; n = 246.
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Figure 11
Figure 11. All anticancer drugs 1940s–2014 by source/year; n = 246.
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Chart 2
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References
This article references 178 other publications.
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  Newman, David J.; Cragg, Gordon M.; Snader, Kenneth M.
  Journal of Natural Products (2003), 66 (7), 1022-1037CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
  A review. This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 yr from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compds. has been introduced, using the concept of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small mol., new chem. entities that are non-synthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are based on the serotonin mol. or derivs. thereof. Finally, although combinatorial techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of a no. of recently approved agents, we have not been able to identify a de novo combinatorial compd. approved as a drug in this time frame.
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3. 3
  Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461– 477 DOI: 10.1021/np068054v
  3
  Natural Products as Sources of New Drugs over the Last 25 Years
  Newman, David J.; Cragg, Gordon M.
  Journal of Natural Products (2007), 70 (3), 461-477CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  A review. This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small mols., 73% are other than "S" (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 25 plus year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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4. 4
  Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311– 335 DOI: 10.1021/np200906s
  4
  Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
  Newman, David J.; Cragg, Gordon M.
  Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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5. 5
  Cragg, G. M.; Newman, D. J. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 3670– 3695 DOI: 10.1016/j.bbagen.2013.02.008
  5
  Natural products: A continuing source of novel drug leads
  Cragg, Gordon M.; Newman, David J.
  Biochimica et Biophysica Acta, General Subjects (2013), 1830 (6), 3670-3695CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
  A review. Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chem. (late 1980s), shifted the focus of drug discovery efforts from Nature to the lab. bench. This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technol. and genome mining. The knowledge gained has allowed unknown mols. to be identified. These novel bioactive structures can be optimized by using combinatorial chem. generating new drug candidates for many diseases. The advent of genetic techniques that permitted the isolation /expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The nos. of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these nos. to the no. of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.
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6. 6
  Newman, D. J.; Giddings, L.-A. Phytochem. Rev. 2014, 13, 123– 137 DOI: 10.1007/s11101-013-9292-6
  6
  Natural products as leads to antitumor drugs
  Newman, David J.; Giddings, Lesley-Ann
  Phytochemistry Reviews (2014), 13 (1), 123-137CODEN: PRHEBS; ISSN:1568-7767. (Springer)
  A review. The discussion in this short review emphasizes that the main and future source of novel natural products as leads to antitumor agents is probably in the areas of biol. that cannot be seen, i.e. the microbial world. The review discusses the role of microbes in the prodn. of secondary metabolites that were initially thought to be from marine invertebrates and goes on to discuss the potential for a no. of known anticancer agents isolated from plant sources to actually be the products of a microbe-plant interaction and finishes with a discussion of the potential of microbial "cryptic clusters" as sources of novel agents/leads to antitumor treatments.
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7. 7
  Newman, D. J.; Cragg, G. M. In Macrocycles in Drug Discovery; RSC Drug Discovery Series No. 40; Levin, J., Ed.; Royal Society of Chemistry: Cambridge, UK, 2014; pp 1– 36.
  There is no corresponding record for this reference.
8. 8
  Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Terrestrial Extremophiles; Springer: Heidelberg, 2015.
  There is no corresponding record for this reference.
9. 9
  Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Marine Extremophiles; Springer: Heidelberg, 2015.
  There is no corresponding record for this reference.
10. 10
  Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Extremophiles, Genomic Studies; Springer: Heidelberg, 2015.
  There is no corresponding record for this reference.
11. 11
  Newman, D. J.; Cragg, G. M.; Kingston, D. G. I. In The Practice of Medicinal Chemistry, 4th ed.; Wermuth, C. G.; Aldous, D.; Raboisson, P.; Rognan, D., Eds.; Elsevier: Amsterdam, 2015; pp 101– 139.
  There is no corresponding record for this reference.
12. 12
  Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740– 6741 DOI: 10.1021/ja016093h
  12
  Use of Biomimetic Diversity-Oriented Synthesis to Discover Galanthamine-Like Molecules with Biological Properties beyond Those of the Natural Product
  Pelish, Henry E.; Westwood, Nicholas J.; Feng, Yan; Kirchhausen, Tomas; Shair, Matthew D.
  Journal of the American Chemical Society (2001), 123 (27), 6740-6741CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A library of mols. based on galanthamine was synthesized using solid-phase biomimetic reactions. The compds. were screened, and secramine (I) was found to be a potent inhibitor of VSVG-GFP movement from the Golgi app. to the plasma membrane.
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13. 13
  Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867– 3870 DOI: 10.1039/b310752n
  There is no corresponding record for this reference.
14. 14
  Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46– 58 DOI: 10.1002/anie.200300626
  14
  A planning strategy for diversity-oriented synthesis
  Burke, Martin D.; Schreiber, Stuart L.
  Angewandte Chemie, International Edition (2004), 43 (1), 46-58CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chem., which aim to access precise or dense regions of chem. space, diversity-oriented synthesis (DOS) populates chem. space broadly with small-mols., having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small mols. having skeletal and stereochem. diversity with defined coordinates in chem. space. Ideally, these pathways also yield compds. having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the mols. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic anal. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic anal. This anal. facilitates synthetic planning, communication, and teaching in this evolving discipline.
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15. 15
  Zhonghong, G.; Reddy, P. T.; Quevillion, S.; Couve-Bonnaire, S.; Ayra, P. Angew. Chem., Int. Ed. 2005, 44, 1366– 1368 DOI: 10.1002/anie.200462298
  There is no corresponding record for this reference.
16. 16
  Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362– 370 DOI: 10.1016/j.cbpa.2010.03.018
  16
  Current strategies for diversity-oriented synthesis
  Dandapani, Sivaraman; Marcaurelle, Lisa A.
  Current Opinion in Chemical Biology (2010), 14 (3), 362-370CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
  A review. Compds. accessed through diversity-oriented synthesis (DOS) are showing promise in modulating the activities of several targets that are currently considered undruggable'. Recently many new DOS pathways have been developed employing multi-component reactions, cycloaddns., ring-closing metathesis and tandem processes. Functional group pairing and build/couple/pair' strategies have been described as a means for generating structural diversity. Efforts have also been directed towards developing DOS libraries based on privileged scaffolds. Recent studies have provided several compelling examples for the utility of DOS compds. for producing novel biol. probes and application of DOS in the context of drug discovery is extremely appealing.
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17. 17
  Reayi, A.; Arya, P. Curr. Opin. Chem. Biol. 2005, 9, 240– 247 DOI: 10.1016/j.cbpa.2005.04.007
  17
  Natural product-like chemical space: search for chemical dissectors of macromolecular interactions
  Reayi, Ayub; Arya, Prabhat
  Current Opinion in Chemical Biology (2005), 9 (3), 240-247CODEN: COCBF4; ISSN:1367-5931. (Elsevier Ltd.)
  A review. Macromol. interactions (i.e. protein-protein or DNA/RNA-protein interactions) play important cellular roles, including cellular communication and programmed cell death. Small-mol. chem. probes are crucial for dissecting these highly organized interactions, for mapping their function at the mol. level and developing new therapeutics. The lack of ideal chem. probes required to understand macromol. interactions is the missing link in the next step of dissecting such interactions. Unfortunately, the classical combinatorial-chem. community has not successfully provided the required probes (i.e. natural product inspired chem. probes that are rich in stereochem. and three-dimensional structural diversity) to achieve these goals. The emerging area of diversity-oriented synthesis (DOS) is beginning to provide natural product-like chem. probes that may be useful in this arena.
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18. 18
  Keller, T. H.; Pichota, A.; Yin, Z. Curr. Opin. Chem. Biol. 2006, 10, 357– 361 DOI: 10.1016/j.cbpa.2006.06.014
  18
  A practical view of druggability
  Keller, Thomas H.; Pichota, Arkadius; Yin, Zheng
  Current Opinion in Chemical Biology (2006), 10 (4), 357-361CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
  A review. The introduction of Lipinski's Rule of Five has initiated a profound shift in the thinking paradigm of medicinal chemists. Understanding the difference between biol. active small mols. and drugs became a priority in the drug discovery process, and the importance of addressing pharmacokinetic properties early during lead optimization is a clear result. These concepts of drug-likeness and druggability have been extended to proteins and genes for target identification and selection. How should these concepts be integrated practically into the drug discovery process. This review summarizes the recent advances in the field and examines the usefulness of the rules of the game in practice from a medicinal chemist's standpoint.
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19. 19
  Lipinski, C. A. Drug Discovery Today: Technol. 2004, 1, 337– 341 DOI: 10.1016/j.ddtec.2004.11.007
  19
  Lead- and drug-like compounds: the rule-of-five revolution
  Lipinski, Christopher A.
  Drug Discovery Today: Technologies (2004), 1 (4), 337-341CODEN: DDTTB5; ISSN:1740-6749. (Elsevier B.V.)
  A review. Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochem. features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clin. success. Physicochem. features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compds. differ from those of drug-like compds. is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chem. tools to probe biol. space. All these topics frame the scope of this short review/perspective.
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20. 20
  Macarron, R. Drug Discovery Today 2006, 11, 277– 279 DOI: 10.1016/j.drudis.2006.02.001
  20
  Critical review of the role of HTS in drug discovery
  Macarron Ricardo
  Drug discovery today (2006), 11 (7-8), 277-9 ISSN:1359-6446.
  'A wise use of lead discovery tactics will distinguish successful drug discovery engines.'
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21. 21
  Koehn, F. E. MedChemComm 2012, 3, 854– 865 DOI: 10.1039/c2md00316c
  21
  Biosynthetic medicinal chemistry of natural product drugs
  Koehn, Frank E.
  MedChemComm (2012), 3 (8), 854-865CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Natural products are an unsurpassed source of lead structures for drug discovery. However, these mols., many of which fall into the beyond-rule-of-5 chem. space, are often difficult to optimize by chem. means because of their complex structures. Biosynthetic engineering of the producing host organism offers an important tool for the modification of complex natural products, leading to analogs which are unattainable by chem. semisynthesis. This review describes the current role of natural products in lead generation and the principles behind biosynthetic medicinal chem. It then goes on to describe five distinct drugs - salinosporamide, geldanamycin, FK506, rapamycin, and epothilone - to exemplify how biosynthetic engineering approaches have contributed to the advancement of natural product clin. candidates.
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22. 22
  Doak, B. C.; Over, B.; Giordanetto, F.; Kihlberg, J. Chem. Biol. 2014, 21, 1115– 1142 DOI: 10.1016/j.chembiol.2014.08.013
  22
  Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
  Doak, Bradley Croy; Over, Bjorn; Giordanetto, Fabrizio; Kihlberg, Jan
  Chemistry & Biology (Oxford, United Kingdom) (2014), 21 (9), 1115-1142CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
  A review. The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compds. with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clin. candidates with mol. wt. (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramol. hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.
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23. 23
  Camp, D.; Garavelas, A.; Campitelli, M. J. Nat. Prod. 2015, 78, 1370– 1382 DOI: 10.1021/acs.jnatprod.5b00255
  There is no corresponding record for this reference.
24. 24
  Macarron, R.; Banks, M. N.; Bojanic, D.; Burns, D. J.; Cirovic, D. A.; Garyantes, T.; Green, D. V. S.; Hertzberg, R. P.; Janzen, W. P.; Paslay, J. W.; Schopfer, U.; Sittampalam, G. S. Nat. Rev. Drug Discovery 2011, 10, 188– 195 DOI: 10.1038/nrd3368
  24
  Impact of high-throughput screening in biomedical research
  Macarron, Ricardo; Banks, Martyn N.; Bojanic, Dejan; Burns, David J.; Cirovic, Dragan A.; Garyantes, Tina; Green, Darren V. S.; Hertzberg, Robert P.; Janzen, William P.; Paslay, Jeff W.; Schopfer, Ulrich; Sittampalam, G. Sitta
  Nature Reviews Drug Discovery (2011), 10 (3), 188-195CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  A review. High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.
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25. 25
  Macarron, R. Nat. Chem. Biol. 2015, 11, 904– 905 DOI: 10.1038/nchembio.1937
  25
  Chemical libraries How dark is HTS dark matter?
  Macarron, Ricardo
  Nature Chemical Biology (2015), 11 (12), 904-905CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  Selecting compds. for the chem. library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many mols. in the Novartis and NIH Mol. Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compds. of interest.
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26. 26
  Wassermann, A. M.; Lounkine, E.; Hoepfner, D.; Le Goff, G.; King, F. J.; Studer, C.; Peltier, J. M.; Grippo, M. L.; Prindle, V.; Tao, J.; Schuffenhauer, A.; Wallace, I. M.; Chen, S.; Krastel, P.; Cobos-Correa, A.; Parker, C. N.; Davies, J. W.; Glick, M. Nat. Chem. Biol. 2015, 11, 958– 966 DOI: 10.1038/nchembio.1936
  26
  Dark chemical matter as a promising starting point for drug lead discovery
  Wassermann Anne Mai; Lounkine Eugen; Le Goff Gaelle; King Frederick J; Peltier John M; Grippo Melissa L; Wallace Iain M; Chen Shanni; Davies John W; Glick Meir; Hoepfner Dominic; Studer Christian; Schuffenhauer Ansgar; Krastel Philipp; Cobos-Correa Amanda; Parker Christian N; King Frederick J; Prindle Vivian; Tao Jianshi
  Nature chemical biology (2015), 11 (12), 958-66 ISSN:.
  High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.
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27. 27
  Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S.-N.; Graham, J.; Pauli, G. F. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b01009
  There is no corresponding record for this reference.
28. 28
  Baell, J.; Walters, M. A. Nature 2014, 513, 481– 483 DOI: 10.1038/513481a
  28
  Chemistry: Chemical con artists foil drug discovery
  Baell, Jonathan; Walters, Michael A.
  Nature (London, United Kingdom) (2014), 513 (7519), 481-483CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  A review. Naivety about promiscuous, assay-duping mols. is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters. Academic drug discoverers must be more vigilant. Mols. that show the strongest activity in screening might not be the best starting points for drugs. PAINS hits should almost always be ignored. Even trained medicinal chemists have to be careful until they become experienced in screening.
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29. 29
  Erlanson, D. A. J. Med. Chem. 2015, 58, 2088– 2090 DOI: 10.1021/acs.jmedchem.5b00294
  There is no corresponding record for this reference.
30. 30
  Ryan, N. J. Drugs 2014, 74, 1709– 1714 DOI: 10.1007/s40265-014-0287-4
  30
  Ataluren: First Global Approval
  Ryan, Nicola J.
  Drugs (2014), 74 (14), 1709-1714CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
  A review. Nonsense mutations are implicated in 5-70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren (Translarna) is an orally available, small mol. compd. that targets nonsense mutations, and is the first drug in its class. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full-length, functional proteins. This article summarizes the milestones in the development of ataluren leading to its conditional first approval for nonsense mutation DMD.
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31. 31
  Hoelder, S.; Clarke, P. A.; Workman, P. Mol. Oncol. 2012, 6, 155– 176 DOI: 10.1016/j.molonc.2012.02.004
  31
  Discovery of small molecule cancer drugs: Successes, challenges and opportunities
  Hoelder, Swen; Clarke, Paul A.; Workman, Paul
  Molecular Oncology (2012), 6 (2), 155-176CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)
  A review. The discovery and development of small mol. cancer drugs has been revolutionized over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalized medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biol. and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small mol. cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chem. hit and lead generation; lead optimization to identify a clin. drug candidate; and finally hypothesis-driven, biomarker-led clin. trials. Although all of these steps are crit., we view target validation and selection and the conduct of biol.-directed clin. trials as esp. important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clin. development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and tech. challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solns. to overcome the Valley of Death' between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalized medicine for cancer patients.
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32. 32
  Bergmann, W.; Feeney, R. J. J. Am. Chem. Soc. 1950, 72, 2809– 2810 DOI: 10.1021/ja01162a543
  32
  Isolation of a new thymine pentoside from sponges
  Bergmann, Werner; Feeney, Robert J.
  Journal of the American Chemical Society (1950), 72 (), 2809-10CODEN: JACSAT; ISSN:0002-7863.
  Extn. of certain air-dried sponges (genus Cryptatothia) in Soxhlet app. with acetone gives crystals, from the boiling solvent, of a mixt. of nucleosides not previously reported. Repeating recrystn. from H2O gives one m. 246-7°, [α]D22 + 80.0° (c, 1.1 in 8% NaOH), [α]D22 + 92° (c, 0.88 in pyridine). Calcd. for C10H14N2O6: C, 46.50; H, 5.48; N, 10.85; Found C, 46.84; H, 5.42; N, 11.09. A neutral aq. soln. absorption spectra gave one max. at 2690 A. (EM 9250). Failure to show spectral response to change in pH is similar to that of thymine desoxyriboside. Vigorous hydrolysis with boiling 10% H2SO4 gave thymine m. 321°. Isolation and identification of the carbohydrate fragment was unsuccessful. To show it is a thymine pentafuranoside, benzoylation by modified Schotten-Baumann gives a tribenzoate m. 190-1°, [α]D22 + 78.3° (c, 0.28 in MeOH), prepd. similarly the tri-p-bromobenzoate m. 223-4° and titration according to the method of Lythgoe and Todd (C.A. 39, 912.1) used 1 mole periodate without formation of formic acid. The proposed name is spongothymidine.
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33. 33
  Bergmann, W.; Feeney, R. J. J. Org. Chem. 1951, 16, 981– 987 DOI: 10.1021/jo01146a023
  There is no corresponding record for this reference.
34. 34
  Bergmann, W.; Burke, D. C. J. Org. Chem. 1955, 20, 1501– 1507 DOI: 10.1021/jo01128a007
  34
  Marine products. XXXIX. The nucleosides of sponges. III. Spongothymidine and spongouridine
  Bergmann, Werner; Burke, Derek C.
  Journal of Organic Chemistry (1955), 20 (), 1501-7CODEN: JOCEAH; ISSN:0022-3263.
  cf. C.A. 46, 5609h; 50, 7808g. Paper chromatography of certain crude fractions of the nucleosides (I) isolated from Crypotethia crypta revealed the presence of spongothymidine (II), spongosine (III), and spongouridine (IV). These I have now been sepd. I are absorbed on a Dowex-1 resin (OH- form) and eluted with a NH4OH-NH4O2CH buffer soln. (pH 9.5) which elutes III. Further elution with a buffer of pH 8.3 gives II, thymine, uracil, and IV in the order given. IV, cubic crystals, m. 226-8°, [α]D 97° (c 0.6, 8% NaOH), 126° (c 1, H2O), pK 9.3. Heating 5 mg. IV with 2 cc. 90% HCO2H 2 hrs. at 150° and paper-chromatographing the product indicate the presence of unchanged IV and some uracil. Refluxing II 3 hrs. in 5% HCl or 5 hrs. in 10% H2SO4, or heating it in a sealed tube 2 hrs. with 10% H2SO4 at 125° or with 5% HCl-MeOH 5 hrs. at 100° leaves II unchanged. Reducing 467 mg. II in 100 cc. liquid NH8 and 5 cc. EtOH with 0.4 g. Na (cf. loc. cit.) and passing the product through Dowex (H+ form) give 400 mg. of a yellow gum (V), [α]D -51°, which by paper chromatography (BuOH-EtOH-H2O and BuOH satd. with H2O) and by ionophoresis in a borate buffer is found to contain only arabinose. When treated with phenylhydrazine V gives a phenylosazone (VI), m. 154-5°, which does not depress the m.p. of the phenylosazone (VII) from ribose. The infrared absorption spectrum of VI is identical with that of VII but differs from that of xylose. Similar reduction of 5.3 mg. IV followed by paper chromatography indicates the presence of arabinose. Periodate oxidation of adenosine, guanosine, cytidine, uridine, II, and IV (20-50 mg.) in H2O with 5 cc. 0.2808N NaIO4 shows the consumption of 1 mole iodate without the formation of HCO2H. Paper ionophoresis of II gives a migration rate of 0.50 for II and 0.68 for IV. Oxidation of 23 mg. II with 1 cc. 0.26N NaIO4 after 24 hrs. gives a soln. with [α]D 16.3°; a similar oxidation of D-glucopyranosylthymine gives a soln. with [α]D 17°; oxidation of 21 mg. IV gives a soln. with [α]D 15°, and oxidation of 25 mg. uridine a soln. with [α]D 15.2°. The results indicate that II is 3-β-D-arabofuranosylthymine and IV is 3-β-D-arabofuranosyluracil.
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35. 35
  Bertin, M. J.; Schwartz, S. L.; Lee, J.; Korobeynikov, A.; Dorrestein, P. C.; Gerwick, L.; Gerwick, W. H. J. Nat. Prod. 2015, 78, 493– 499 DOI: 10.1021/np5009762
  35
  Spongosine production by a Vibrio harveyi strain associated with the sponge Tectitethya crypta
  Bertin, Matthew J.; Schwartz, Sarah L.; Lee, John; Korobeynikov, Anton; Dorrestein, Pieter C.; Gerwick, Lena; Gerwick, William H.
  Journal of Natural Products (2015), 78 (3), 493-499CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  Spongosine (I), deoxyspongosine, spongothymidine (Ara T), and spongouridine (Ara U) were isolated from the Caribbean sponge Tectitethya crypta and given the general name "spongonucleosides". Spongosine, a methoxyadenosine deriv., has demonstrated a diverse bioactivity profile including anti-inflammatory activity and analgesic and vasodilation properties. Investigations into unusual nucleoside prodn. by T. crypta-assocd. microorganisms using mass spectrometric techniques have identified a spongosine-producing strain of Vibrio harveyi and several structurally related compds. from multiple strains.
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36. 36
  Szychowski, J.; Truchon, J.-F.; Bennani, Y. L. J. Med. Chem. 2014, 57, 9292– 9308 DOI: 10.1021/jm500941m
  36
  Natural Products in Medicine: Transformational Outcome of Synthetic Chemistry
  Szychowski, Janek; Truchon, Jean-Francois; Bennani, Youssef L.
  Journal of Medicinal Chemistry (2014), 57 (22), 9292-9308CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chem. transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Mol. modeling or X-ray structures of NP/protein complexes supporting the obsd. boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chem., in structure detn., and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivs.
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37. 37
  Bathula, S. R.; Akondi, S. M.; Mainkar, P. S.; Chandrasekhar, S. Org. Biomol. Chem. 2015, 13, 6432– 6448 DOI: 10.1039/C5OB00403A
  There is no corresponding record for this reference.
38. 38
  Thaker, M. N.; Wright, G. D. ACS Synth. Biol. 2015, 4, 195– 206 DOI: 10.1021/sb300092n
  38
  Opportunities for Synthetic Biology in Antibiotics: Expanding Glycopeptide Chemical Diversity
  Thaker, Maulik N.; Wright, Gerard D.
  ACS Synthetic Biology (2015), 4 (3), 195-206CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
  A review. Synthetic biol. offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clin. use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biol. thinking and strategies can provide new mols. and expand chem. diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biol. can expand antibiotic chem. diversity to help address the growing resistance crisis.
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39. 39
  Stockdale, T. P.; Williams, C. M. Chem. Soc. Rev. 2015, 44, 7737– 7763 DOI: 10.1039/C4CS00477A
  39
  Pharmaceuticals that contain polycyclic hydrocarbon scaffolds
  Stockdale, Tegan P.; Williams, Craig M.
  Chemical Society Reviews (2015), 44 (21), 7737-7763CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  Numerous variations on structural motifs exist within pharmaceutical compds. that have entered the clinic. These variations have amounted over many decades based on years of drug development assocd. with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approx. 20 all carbon cage contg. pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs contg. the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurol. activity. In addn., to an extensive overview of the history and biol. assocd. with each drug, a survey of synthetic methods used to construct these entities is presented. An anal. section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.
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40. 40
  Yoganathan, S.; Miller, S. J. J. Med. Chem. 2015, 58, 2367– 2377 DOI: 10.1021/jm501872s
  40
  Structure Diversification of Vancomycin through Peptide-Catalyzed, Site-Selective Lipidation: A Catalysis-Based Approach To Combat Glycopeptide-Resistant Pathogens
  Yoganathan, Sabesan; Miller, Scott J.
  Journal of Medicinal Chemistry (2015), 58 (5), 2367-2377CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, the authors disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. The authors have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliph. hydroxyls on vancomycin, generating three new derivs. Incorporation of lipid chains into the vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for the new derivs. against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. The authors have also performed a structure-activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.
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41. 41
  Novaes, L. F. T.; Avila, C. M.; Pelizzaro-Rocha, K. J.; Vendramini-Costa, D. B.; Dias, M. P.; Trivella, D. B. B.; de Carvalho, J. E.; Ferreira-Halder, C. V.; Pilli, R. A. ChemMedChem 2015, 10, 1687– 1699 DOI: 10.1002/cmdc.201500246
  There is no corresponding record for this reference.
42. 42
  Nicolaou, K. C. Chem. Biol. 2014, 21, 1039– 1045 DOI: 10.1016/j.chembiol.2014.07.020
  42
  The Chemistry-Biology-Medicine Continuum and the Drug Discovery and Development Process in Academia
  Nicolaou, K. C.
  Chemistry & Biology (Oxford, United Kingdom) (2014), 21 (9), 1039-1045CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
  A review. Admirable as it is, the drug discovery and development process is continuously undergoing changes and adjustments in search of further improvements in efficiency, productivity, and profitability. Recent trends in academic-industrial partnerships promise to provide new opportunities for advancements of this process through transdisciplinary collaborations along the entire spectrum of activities involved in this complex process. This perspective discusses ways to promote the emerging academic paradigm of the chem.-biol.-medicine continuum as a means to advance the drug discovery and development process.
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  Allen, R. C. In Annual Reports in Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: Orlando, 1984; Vol. 19, pp 313– 326.
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44. 44
  Allen, R. C. In Annual Reports in Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: Orlando, 1985; Vol. 20, pp 315– 325.
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45. 45
  Allen, R. C. In Annual Reports in Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: Orlando, 1986; Vol. 21, pp 323– 335.
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46. 46
  Allen, R. C. In Annual Reports in Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: Orlando, 1987; Vol. 22, pp 315– 330.
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47. 47
  Ong, H. H.; Allen, R. C. In Annual Reports in Medicinal Chemistry; Allen, R. C., Ed.; Academic Press: San Diego, 1988; Vol. 23, pp 325– 348.
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  Ong, H. H.; Allen, R. C. In Annual Reports in Medicinal Chemistry; Allen, R. C., Ed.; Academic Press: San Diego, 1989; Vol. 24, pp 295– 315.
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  Ong, H. H.; Allen, R. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1990; Vol. 25, pp 309– 322.
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  Strupczewski, J. D.; Ellis, D. B.; Allen, R. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1991; Vol. 26, pp 297– 313.
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  Strupczewski, J. D.; Ellis, D. B. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1992; Vol. 27, pp 321– 337.
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  Strupczewski, J. D.; Ellis, D. B. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1993; Vol. 28, pp 325– 341.
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  Cheng, X.-M. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, 1994; Vol. 29, pp 331– 354.
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  Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. In Annual Reports in Medicinal Chemistry; Desai, M. C., Ed.; Academic Press: Amsterdam, 2012; Vol. 47, pp 499– 569.
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  Bronson, J.; Black, A.; Dhar, T. G. M.; Ellsworth, B. A.; Merritt, J. R. In Annual Reports in Medicinal Chemistry; Desai, M. C., Ed.; Academic Press: Amsterdam, 2013; Vol. 48, pp 471– 546.
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  Bronson, J.; Black, A.; Dhar, M.; Ellsworth, B.; Merritt, J. R. In Annual Reports in Medicinal Chemistry; Desai, M. C., Ed.; Academic Press: Amsterdam, 2014; Vol. 49, pp 437– 508.
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  Bronson, J.; Black, A.; Dhar, M.; Ellsworth, B. A.; Merritt, J. R.; Peese, K.; Pashine, A. In 2015 Medicinal Chemistry Reviews; Desai, M. C., Ed.; Medicinal Chemistry Division ACS: Washington DC, 2015; Vol. 50, pp 461– 576.
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  Prous, J. R. Drug News Persp 1994, 7, 26– 36
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  Prous, J. R. Drug News Persp. 1996, 9, 19– 32
  81
  The year's new drugs
  Prous, J. R.
  Drug News & Perspectives (1996), 9 (1), 19-32CODEN: DNPEED; ISSN:0214-0934. (Prous)
  A review without refs. on the historical and research perspective on th 40 new products that reached their first markets in 1995, including ten breakthrough products approved for the first time (data from the Prous Science database). The drugs covered include analgesic, anesthetic, neurol., respiratory, gastrointestinal and endocrine drugs, agents affecting blood coagulation, antiinfective therapy and immunomodulators and oncolytic drugs, treatment of poisoning and drug dependency, as well as diagnostic agents.
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  Graul, A. I. Drug News Persp. 1997, 10, 5– 18
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  Graul, A. I. Drug News Persp. 1998, 11, 15– 32
  83
  The year's new drugs
  Graul A I
  Drug news & perspectives (1998), 11 (1), 15-32 ISSN:0214-0934.
  There is no expanded citation for this reference.
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84. 84
  Graul, A. I. Drug News Persp. 1999, 12, 27– 43
  84
  The year's new drugs
  Graul, Ann I.
  Drug News & Perspectives (1999), 12 (1), 27-43CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review with no refs. Forty-two new chem. entities and biol. drugs and four diagnostic agents reached their first markets in 1998. During the past year, Agents Affecting Blood Coagulation and Metabolic Drugs were the most active therapeutic groups in terms of new launches, with six market introductions each. There were also six new launches in the category of Antiinfective Therapy, including two in the area of AIDS Medicines. The United States was the most active market for new products, with a total of 28 new launches in 1998, constituting 67% of the total of new introductions for the year.
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85. 85
  Graul, A. I. Drug News Persp. 2000, 13, 37– 53
  85
  The year's new drugs
  Graul, Ann I.
  Drug News & Perspectives (2000), 13 (1), 37-53CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review with no refs. Forty-four new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 1999. Endocrine Drugs was the most active therapeutic group in terms of new launches, with nine market introductions, and the United States was once again the most active market for new products, with a total of 23 new launches in 1999, constituting 50% of all new introductions for the year.
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86. 86
  Graul, A. I. Drug News Persp. 2001, 14, 12– 31
  86
  The year's new drugs
  Graul, Ann I.
  Drug News & Perspectives (2001), 14 (1), 12-31CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. Forty-four new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 2000. Gastrointestinal Drugs was the most active therapeutic group in terms of new launches, with seven market introductions, and the United States was once again the most active single market for new products, with a total of 17 new launches in 2000, constituting 37% of all new introductions for the year.
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87. 87
  Graul, A. I. Drug News Persp. 2002, 15, 29– 43
  87
  The Year's New Drugs
  Graul Ann I.
  Drug news & perspectives (2002), 15 (1), 29-43 ISSN:0214-0934.
  Thirty-four new chemical entities and biological drugs and two diagnostic agents reached their first markets in 2001. Antiinfective Therapy was the most active therapeutic group in terms of new launches, with five market introductions, and the United States was the most active single market for new products, with a total of 15 new launches in 2001, constituting 43% of all new introductions for the year. (c) 2002 Prous Science. All rights reserved.
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88. 88
  Graul, A. I. Drug News Persp. 2003, 16, 22– 39
  88
  The year's new drugs
  Graul Ann I
  Drug news & perspectives (2003), 16 (1), 22-39 ISSN:0214-0934.
  The United States was the most active market for new product launches (22 products, 62.5%) in a year that saw 35 new chemical entities and biological drugs and two diagnostic agents reach their first markets. The most active therapeutic groups were anti-infective, oncolytic and metabolic drugs with five launches for each.
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89. 89
  Graul, A. I. Drug News Persp. 2004, 17, 43– 57
  89
  The year's new drugs
  Graul, Ann I.
  Drug News & Perspectives (2004), 17 (1), 43-57CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. Inaugurated 16 yr ago, this annual article provides the opportunity to present from both a historical and a research perspective those mol. entities and biol. drugs that were launched or approved in various countries for the first time during the past year. According to our records, 30 new chem. entities and biol. drugs and two diagnostic agents reached their first markets in 2003. Another six new products were approved for the first time in 2003 but were not launched before year-end. During the past year, Endocrine and Metabolic Drugs was the most active therapeutic group in terms of new launches, with six market introductions. The United States was again the most active market for new products, with a total of 20 new launches in 2003, constituting 66.6% of the total of new introductions for the year.
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90. 90
  Graul, A. I.; Prous, J. R. Drug News Persp. 2005, 18, 21– 36
  90
  A historical and research perspective on the 23 new products that reached their first markets in 2004. The year's new drugs
  Graul, Ann I.; Prous, J. R.
  Drug News & Perspectives (2005), 18 (1), 21-36CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. Twenty-three new biol. drugs and diagnostic agents reached their first markets in 2004. The oncolytic drugs therapeutic group was the most active in terms of new launches, with seven market introductions, and the United States was the most active single market for new products, with a total of 10 new launches in 2004.
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91. 91
  Graul, A. I.; Prous, J. R. Drug News Persp. 2006, 19, 33– 53
  91
  The year's new drugs
  Graul, Ann I.; Prous, J. R.
  Drug News & Perspectives (2006), 19 (1), 33-53CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. Forty-one new biol. drugs and diagnostic agents reached their first markets in 2005. Antiinfective therapy, immunomodulators and agents for immunization and central nervous system drugs were the most active therapeutic groups in terms of new chem. entities launched for the first time, with six market introductions apiece. The United States was again the most active market for new products, with a total of 21 new launches in 2005, constituting 50% of the total of new introductions for the year.
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92. 92
  Graul, A. I.; Sorbera, L. A.; Bozzo, J.; Serradell, N.; Revel, L.; Prous, J. R. Drug News Persp. 2007, 20, 17– 44
  92
  The year's new drugs and biologics-2006
  Graul, A. I.; Sorbera, L. A.; Bozzo, J.; Serradell, N.; Revel, L.; Prous, J. R.
  Drug News & Perspectives (2007), 20 (1), 17-44CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines-this figure includes both drugs and biologies for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine-reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year's edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an anal. of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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93. 93
  Graul, A. I.; Prous, J. R.; Barrionuevo, M.; Bozzo, J.; Castañer, R.; Cruces, E.; Revel, L.; Rosa, E.; Serradell, N.; Sorbera, L. A. Drug News Persp. 2008, 21, 7– 35
  93
  The year's new drugs and biologics-2007
  Graul, A. I.; Prous, J. R.; Barrionuevo, M.; Bozzo, J.; Castaner, R.; Cruces, E.; Revel, L.; Rosa, E.; Serradell, N.; Sorbera, L. A.
  Drug News & Perspectives (2008), 21 (1), 7-35CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2007, 30 new medicines-this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents-reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for 45% of the new medicines launched in 2007. Several new features were introduced last year, and have been maintained due to a high level of interest from readers: a deeper insight into the three first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life span of medicines; and an anal. of the market for these new medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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94. 94
  Graul, A. I.; Revel, L.; Barrionuevo, M.; Cruces, E.; Rosa, E.; Vergés, C.; Lupone, B.; Diaz, N.; Castañe, R. Drug News Perspect. 2009, 22, 7– 27 DOI: 10.1358/dnp.2009.22.1.1303754
  94
  The year's new drugs & biologics - 2008
  Graul, Ann I.; Revel, Laura; Barrionuevo, Meritxell; Cruces, Elisabet; Rosa, Esmeralda; Verges, Clara; Lupone, Becky; Diaz, Nuria; Castaner, Rosa
  Drug News & Perspectives (2009), 22 (1), 7-29CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2008, 31 new medicines-this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents-reached their first markets. Line extensions (new indications, new formulations and new combinations of previously marketed products) accounted for more than one-third of the new medicines launched in 2008. In addn. to providing an overview of all drugs and biologies launched or approved for the first time ever in the previous year, this article will also review in further depth the first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; and a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
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95. 95
  Graul, A. I.; Sorbera, L. A.; Pina, P.; Tell, M.; Cruces, E.; Rosa, E.; Stringer, M.; Castañer, R.; Revel, L. Drug News Perspect. 2010, 23, 7– 36 DOI: 10.1358/dnp.2010.23.1.1440373
  95
  The year's new drugs & biologics - 2009
  Graul, Ann I.; Sorbera, Lisa; Pina, Patricia; Tell, Montse; Cruses, Elisabet; Rosa, Esmeralda; Stringer, Mark; Castaner, Rosa; Revel, Laura
  Drug News & Perspectives (2010), 23 (1), 7-36CODEN: DNPEED; ISSN:0214-0934. (Prous Science)
  A review. This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2009, 51 new medicines and vaccines reached their first markets. Line extensions (new indications, new formulations and new combinations of previously marketed products) accounted for more than 30% of the new products launched in 2009. In addn. to providing an overview of all drugs and biologics launched or approved for the first time ever in the previous year, this article will also review in further depth the first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an anal. of the discovery and development periods for the year's new products; and a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines. We also provide a brief glimpse at selected drugs and biologies which could reach their first markets in the foreseeable future.
  >> More from SciFinder ^®
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96. 96
  Graul, A. I.; Cruces, E. Drugs Today 2011, 47, 27– 51 DOI: 10.1358/dot.2011.47.1.1587820
  96
  The year's new drugs & biologics, 2010
  Graul, A. I.; Cruces, E.
  Drugs of Today (2011), 47 (1), 27-51CODEN: MDACAP; ISSN:1699-3993. (Prous Science)
  A review. The year 2010 marked the first launch for a no. of new drugs and biologics, including several important innovations and therapeutic advances. Twenty-nine new chem. entities and biologics for therapeutic use reached their first markets in 2010. Following a growing tendency in recent years, at least 20 important line extensions were also introduced last year. Both figures are significantly lower than those registered in 2009. Pharma and biotech companies also became leaner and more competitive in 2010 through two processes: prioritizing R&D and discontinuing less promising projects, and merging with or acquiring companies with complementary strengths and weaknesses. This review provides a brief overview of the highlights of 2010.
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97. 97
  Graul, A. I.; Cruces, E.; Dulsat, C.; Arias, E.; Stringer, M. Drugs Today 2012, 48, 33– 77 DOI: 10.1358/dot.2012.48.1.1769676
  97
  The Year's new drugs & biologics, 2011
  Graul, A. I.; Cruces, E.; Dulsat, C.; Arias, E.; Stringer, M.
  Drugs of Today (2012), 48 (1), 33-77CODEN: MDACAP; ISSN:1699-3993. (Thomson Reuters)
  A review. 2011 Was a good year in many respects for the pharmaceutical industry, esp. regarding the approval and launch of several important new products. The FDA reported a record high rate of approvals during FY2011 (Oct. 1, 2010-Sept. 30, 2011), reflecting the agency's commitment to maintaining "a state-of-the-art drug approval process that brings important drugs to market quickly and efficiently" (1). While not all of the new drugs and biologics listed in FDA's fiscal year summary meet the criteria for inclusion in this article, most of them do, and hence are reviewed in the following pages. Also covered in this year's expanded article are new approvals and new launches in other global markets, line extensions and other developments of interest to the industry: generic drug approvals, product withdrawals and discontinuations, new developments in the area of orphan drugs and diseases, and more.
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98. 98
  Graul, A. I.; Lupone, B.; Cruces, E.; Stringer, M. Drugs Today 2013, 49, 33– 38
  98
  2012 in review - part I: the year's new drugs & biologics
  Graul A I; Lupone B; Cruces E; Stringer M
  Drugs of today (Barcelona, Spain : 1998) (2013), 49 (1), 33-68 ISSN:1699-3993.
  Thirty-seven new launches are considered in the first part of this annual review article, including 36 drugs and biologics that reached their first markets worldwide in 2012 and one additional drug that was launched at the end of December 2011. In addition, 26 significant new line extensions (new indications, new formulations and new combinations of existing drugs) that were launched for the first time in 2012 are discussed in this review. Also included are new drugs and biologics and new line extensions that were approved for the first time between January and December 2012, although they were not launched before the end of the year.
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99. 99
  Graul, A. I.; Cruces, E.; Stringer, M. Drugs Today 2014, 50, 51– 100 DOI: 10.1358/dot.2014.50.1.2116673
  99
  The year's new drugs & biologics, 2013: Part I
  Graul A I; Cruces E; Stringer M
  Drugs of today (Barcelona, Spain : 1998) (2014), 50 (1), 51-100 ISSN:1699-3993.
  This article provides a comprehensive overview of the 56 new drugs and biologics introduced for the first time in 2013, the largest number in at least a decade. This includes 20 new orphan drugs and 10 first-in-class agents, as well as the first three products bearing the FDA's new Breakthrough Therapy Designation. The review also covers 30 important new line extensions, encompassing new indications, new formulations and new combinations of previously marketed agents. In addition to this bumper crop of new launches, another 19 products were approved for the first time during the year but not yet launched by the close of this article; these new products are also discussed.
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100. 100
  Graul, A. I.; Navarro, D.; Dulsat, G.; Cruces, E.; Tracy, M. Drugs Today 2014, 50, 133– 158 DOI: 10.1358/dot.2014.50.2.2122810
  100
  The year's new drugs & biologics, 2013: Part II
  Graul A I; Navarro D; Dulsat C; Cruces E; Tracy M
  Drugs of today (Barcelona, Spain : 1998) (2014), 50 (2), 133-58 ISSN:1699-3993.
  The demise of the pharmaceutical industry, so pessimistically predicted by many in recent years, has not come to pass and in fact the patient is alive and well. New programs enacted by drug regulators have been enthusiastically taken up by the industry, including the FDA's breakthrough therapy and qualified infectious disease product (QIDP) designations, as well as the now-consolidated orphan drug programs in many countries. Pharma companies pragmatically wean nonperformers from the pipeline in an efficient manner, resulting in somewhat leaner but higher-quality pipelines. Mergers and acquisitions also continue to drive consolidation and efficiency in the industry, a trend that continued during 2013. This article provides an updated review of these and other trends in the pharmaceutical industry in the year just passed.
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101. 101
  Graul, A. I.; Stringer, M. Drugs Today 2015, 51, 37– 87 DOI: 10.1358/dot.2015.51.1.2279964
  101
  The year's new drugs & biologics, 2014: Part I
  Graul A I; Cruces E; Stringer M
  Drugs of today (Barcelona, Spain : 1998) (2015), 51 (1), 37-87 ISSN:1699-3993.
  A year-end wrap-up of new drug approvals and launches reveals that activity in the pharmaceutical industry continues at a high level, with 55 new drugs and biologics introduced on their first markets in 2014 (as of December 23, 2014). Additionally, 29 important new line extensions (new formulations, new combinations or new indications for previously marketed products) also reached their first markets during the year. The most active therapeutic group in terms of new launches was anti-infective therapies, with 11 new drugs and biologics launched, most for the treatment of multidrug-resistant bacterial infections or hepatitis C. The most active market for new launches was again the U.S., site of more than half of all new launches in 2014. However new launch activity increased considerably last year in Japan, which actually pulled ahead of the E.U. for the first time in many years. In another important new development, 15 of the new drugs and biologics launched last year had orphan drug status, 5 had breakthrough therapy designation and 3 had Qualified Infectious Disease Product (QIDP) status. Another 19 products were approved for the first time during the year but not yet launched by close of this article; most are slated for launch in the first months of the new year.
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102. 102
  Newman, D. J.; Cragg, G. M.; O’Keefe, B. R. In Modern Biopharmaceuticals, Design, Development and Optimization; Knablein, J., Ed.; Wiley-VCH: Weinheim, 2005; Vol. 2, pp 451– 496.
  There is no corresponding record for this reference.
103. 103
  Boyd, M. R. In Current Therapy in Oncology; Neiderhuber, J., Ed.; Decker: Philadelphia, 1993; pp 11– 22.
  There is no corresponding record for this reference.
104. 104
  Cole, W. H. Chemotherapy of Cancer; Lea and Febiger: Philadelphia, 1970; p 349.
  There is no corresponding record for this reference.
105. 105
  Sweetman, S. C. Martindale, The Complete Drug Reference, 33rd ed.; The Pharmaceutical Press: London, 2002.
  There is no corresponding record for this reference.
106. 106
  Fabbro, D.; Cowan-Jacob, S. W.; Moebitz, H. Br. J. Pharmacol. 2015, 172, 2675– 2700 DOI: 10.1111/bph.13096
  106
  Ten things you should know about protein kinases: IUPHAR Review 14
  Fabbro, Doriano; Cowan-Jacob, Sandra W.; Moebitz, Henrik
  British Journal of Pharmacology (2015), 172 (11), 2675-2700CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  Many human malignancies are assocd. with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on 'the 10 things you should know about protein kinases and their inhibitors', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the '10 things' have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncol. indications.
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107. 107
  Fabbro, D.; Ruetz, S.; Buchdunger, E.; Cowan-Jacob, S. W.; Fendrich, G.; Liebtanz, J.; Mestan, J.; O’Reilly, T.; Traxler, P.; Chaudhuri, B.; Fretz, H.; Zimmermann, J.; Meyer, T.; Caravatti, G.; Furet, P.; Manley, P. W. Pharmacol. Ther. 2002, 93, 79– 98 DOI: 10.1016/S0163-7258(02)00179-1
  107
  Protein kinases as targets for anticancer agents: from inhibitors to useful drugs
  Fabbro, Doriano; Ruetz, Stephan; Buchdunger, Elisabeth; Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Liebetanz, Janis; Mestan, Jurgen; O'Reilly, Terence; Traxler, Peter; Chaudhuri, Bhabatosh; Fretz, Heinz; Zimmermann, Jurg; Meyer, Thomas; Caravatti, Giorgio; Furet, Pascal; Manley, Paul W.
  Pharmacology & Therapeutics (2002), 93 (2-3), 79-98CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science Inc.)
  A review. Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biol. processes, such as control of cell growth, metab., differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-mol. wt. therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clin. trials). Three examples of inhibitors of protein kinases are reviewed, including low-mol. wt. compds. targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrrolopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec, Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear assocn. with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clin. utility of protein kinase inhibitors as therapeutic agents. In a preclin. model, STI571 (Glivec, Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematol. and cytogenetic responses in CML and clin. responses in the c-Kit-driven gastrointestinal tumors.
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108. 108
  Vijayan, R. S. K.; He, P.; Modi, V.; Duong-Ly, K. C.; Ma, H.; Peterson, J. R.; Dunbrack, J. R. L.; Levy, R. M. J. Med. Chem. 2015, 58, 466– 479 DOI: 10.1021/jm501603h
  There is no corresponding record for this reference.
109. 109
  Tiligada, E.; Ishii, M.; Riccardi, C.; Spedding, M.; Simon, H.-U.; Teixeira, M. M.; Cuervo, M. L. C.; Holgate, S. T.; Levi-Schaffer, F. Br. J. Pharmacol. 2015, 172, 4217– 4227 DOI: 10.1111/bph.13219
  109
  The expanding role of immunopharmacology - IUPHAR Review 16
  Tiligada, Ekaterini; Ishii, Masaru; Riccardi, Carlo; Spedding, Michael; Simon, Hans-Uwe; Teixeira, Mauro Martins; Landys Chovel Cuervo, Mario; Holgate, Stephen T.; Levi-Schaffer, Francesca
  British Journal of Pharmacology (2015), 172 (17), 4217-4227CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacol. research have made available new classes of clin. relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a no. of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacol. is presently considered as one of the expanding fields of pharmacol. Immunopharmacol. addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clin. needs. While in the near future a no. of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunol., pharmacol. and drug discovery. The newly formed ImmuPhar () is the Immunopharmacol. Section of the International Union of Basic and Clin. Pharmacol. (IUPHAR, ). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiol. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.
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110. 110
  Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.; Hirshfield, J.; Veber, D. F. J. Org. Chem. 1985, 50, 4615– 4625 DOI: 10.1021/jo00223a037
  There is no corresponding record for this reference.
111. 111
  DeSolms, S. J.; Giuliani, E. A.; Guare, J. P.; Vacca, J. P.; Sanders, W. M.; Graham, S. L.; Wiggins, J. M.; Darke, P. L.; Sigal, I. S. J. Med. Chem. 1991, 34, 2852– 2857 DOI: 10.1021/jm00113a025
  There is no corresponding record for this reference.
112. 112
  Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 4, 439– 452 DOI: 10.1016/S1367-5931(98)80119-1
  There is no corresponding record for this reference.
113. 113
  Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun. 1967, 27, 157– 162 DOI: 10.1016/S0006-291X(67)80055-X
  There is no corresponding record for this reference.
114. 114
  Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.; Cohen, N.-C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G. Chem. Biol. 2000, 7, 493– 504 DOI: 10.1016/S1074-5521(00)00134-4
  114
  Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin
  Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.; Cohen, N-C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G.
  Chemistry & Biology (2000), 7 (7), 493-504CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)
  Background: The aspartic proteinase renin plays an important physiol. role in the regulation of blood pressure. It catalyzes the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compds. has made it to the end of clin. trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. Results: Crystal structure anal. of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chem. optimization process. Structure anal. revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addn., however, these compds. interact with a hitherto unrecognized large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to the S3sp sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3sp were optimized. Conclusions: Our design approach led to compds. with high in vitro affinity and specificity for renin, favorable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
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115. 115
  Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; Cohen, N.-C.; Rasetti, V.; Ruger, H.; Goschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.; Herold, P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A.; Bedigian, M. P. Biochem. Biophys. Res. Commun. 2003, 308, 698– 705 DOI: 10.1016/S0006-291X(03)01451-7
  There is no corresponding record for this reference.
116. 116
  Webb, R. L.; Schiering, N.; Sedrani, R.; Maibaum, J. J. Med. Chem. 2010, 53, 7490– 7520 DOI: 10.1021/jm901885s
  There is no corresponding record for this reference.
117. 117
  Politi, A.; Leonis, G.; Tzoupis, H.; Ntountaniotis, D.; Papadopoulos, M. G.; Grdadolnik, S. G.; Mavromoustakos, T. Mol. Inf. 2011, 30, 973– 985 DOI: 10.1002/minf.201100077
  117
  Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site
  Politi, Aggeliki; Leonis, Georgios; Tzoupis, Haralambos; Ntountaniotis, Dimitrios; Papadopoulos, Manthos G.; Grdadolnik, Simona Golic; Mavromoustakos, Thomas
  Molecular Informatics (2011), 30 (11-12), 973-985CODEN: MIONBS; ISSN:1868-1743. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational anal. were explored using 1D and 2D NMR spectroscopy, as well as random search and mol. dynamics (MD) simulations. For the first time, MD calcns. have also been performed for aliskiren at the receptor site, in order to reveal its mol. basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that dets. the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Addnl. mol. mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calcns. for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.
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118. 118
  Tzoupis, H.; Leonis, G.; Megariotis, G.; Supuran, C. T.; Mavromoustakos, T.; Papadopoulos, M. G. J. Med. Chem. 2012, 55, 5784– 5796 DOI: 10.1021/jm300180r
  There is no corresponding record for this reference.
119. 119
  Palomo, J. M. RSC Adv. 2014, 4, 32658– 32672 DOI: 10.1039/C4RA02458C
  119
  Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides
  Palomo, Jose M.
  RSC Advances (2014), 4 (62), 32658-32672CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A review. This review article highlights the strategies to successfully perform an efficient solid-phase synthesis of complex peptides including posttranslational modifications, fluorescent labels, and reporters or linking groups of exceptional value for biol. studies of several important diseases. The solid-phase approach is the best alternative to synthesize these peptides rapidly and in high amts. The key aspects that need to be considered when performing a peptide synthesis in solid phase of these mols. are discussed.
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120. 120
  Over, B.; Wetzel, S.; Grutter, C.; Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2013, 5, 21– 28 DOI: 10.1038/nchem.1506
  120
  Natural-product-derived fragments for fragment-based ligand discovery
  Over, Bjoern; Wetzel, Stefan; Gruetter, Christian; Nakai, Yasushi; Renner, Steffen; Rauh, Daniel; Waldmann, Herbert
  Nature Chemistry (2013), 5 (1), 21-28CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
  Fragment-based ligand and drug discovery predominantly employs sp2-rich compds. covering well-explored regions of chem. space. Despite the ease with which such fragments can be coupled, this focus on flat compds. is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biol. validated natural products are rich in stereogenic centers and populate areas of chem. space not occupied by av. synthetic mols. Here, we have analyzed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centers. The structures of the cluster centers differ from previously explored fragment libraries, but for nearly half of the clusters representative members are com. available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallog. and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.
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121. 121
  Bauer, A.; Bronstrup, M. Nat. Prod. Rep. 2014, 31, 35– 60 DOI: 10.1039/C3NP70058E
  121
  Industrial natural product chemistry for drug discovery and development
  Bauer, Armin; Broenstrup, Mark
  Natural Product Reports (2014), 31 (1), 35-60CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. In addn. to their prominent role in basic biol. and chem. research, natural products are a rich source of com. products for the pharmaceutical and other industries. Industrial natural product chem. is of fundamental importance for successful product development, as the vast majority (ca. 80%) of com. drugs derived from natural products require synthetic efforts, either to enable economical access to bulk material, and/or to optimize drug properties through structural modifications. This review aims to illustrate issues on the pathway from lead to product, and how they have been successfully addressed by modern natural product chem. It is focused on natural products of current relevance that are, or are intended to be, used as pharmaceuticals.
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122. 122
  Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Nat. Prod. Rep. 2014, 31, 419– 432 DOI: 10.1039/C3NP70090A
  122
  Natural product synthesis in the age of scalability
  Kuttruff, Christian A.; Eastgate, Martin D.; Baran, Phil S.
  Natural Product Reports (2014), 31 (4), 419-432CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. The ability to procure useful quantities of a mol. by simple, scalable routes is emerging as an important goal in natural product synthesis. Approaches to mols. that yield substantial material enable collaborative investigations (such as SAR studies or eventual com. prodn.) and inherently spur innovation in chem. As such, when evaluating a natural product synthesis, scalability is becoming an increasingly important factor. This highlight discussed recent examples of natural product synthesis from the authors' lab. and others, where the prepn. of gram-scale quantities of a target compd. or a key intermediate allowed for a deeper understanding of biol. activities or enabled further investigational collaborations.
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123. 123
  Maier, M. E. Org. Biomol. Chem. 2015, 13, 5302– 5345 DOI: 10.1039/C5OB00169B
  There is no corresponding record for this reference.
124. 124
  Liu, Y.-Y.; Wang, Y.; Walsh, T. R.; Yi, L.-X.; Zhang, R.; Spencer, J.; Doi, Y.; Tian, G.; Dong, B.; Huang, X.; Yu, L.-F.; Gu, D.; Ren, H.; Chen, X.; Lv, L.; He, D.; Zhou, H.; Liang, Z.; Liu, J.-H.; Shen, J. Lancet Infect. Dis. 2015, DOI: 10.1016/S1473-3099(15)00424-7
  There is no corresponding record for this reference.
125. 125
  Hütter, R.; Keller-Schien, W.; Knüsel, F.; Prelog, V.; Rodgers, G. C., jr.; Suter, P.; Vogel, G.; Voser, W.; Zähner, H. Helv. Chim. Acta 1967, 50, 1533– 1539 DOI: 10.1002/hlca.19670500612
  There is no corresponding record for this reference.
126. 126
  Kohno, J.; Kawahata, T.; Otake, T.; Morimoto, M.; Mori, H.; Ueba, N.; Nishio, M.; Kinumaki, A.; Komatsubara, S.; Kawashima, K. Biosci., Biotechnol., Biochem. 1996, 60, 1036– 1037 DOI: 10.1271/bbb.60.1036
  There is no corresponding record for this reference.
127. 127
  Camp, D. Drugs Future 2013, 38, 245– 256 DOI: 10.1358/dof.2013.038.04.1940442
  There is no corresponding record for this reference.
128. 128
  Kantarjian, H. M.; O’Brien, S.; Cortes, J. Clin. Lymphoma, Myeloma Leuk. 2013, 13, 530– 533 DOI: 10.1016/j.clml.2013.03.017
  128
  Homoharringtonine/Omacetaxine Mepesuccinate: The Long and Winding Road to Food and Drug Administration Approval
  Kantarjian, Hagop M.; O'Brien, Susan; Cortes, Jorge
  Clinical Lymphoma, Myeloma & Leukemia (2013), 13 (5), 530-533CODEN: CLMLCQ; ISSN:2152-2669. (Elsevier)
  A review. Homoharringtonine/omacetaxine is a unique agent with a long history of research development. It has been recently approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia after failure of 2 or more tyrosine kinase inhibitors. Research with this agent has spanned over 40 years, with many instructive lessons to cancer research, which are summarized in this review.
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129. 129
  Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396– 407 DOI: 10.1038/nchembio.2007.1
  129
  Modern synthetic efforts toward biologically active terpenes
  Maimone, Thomas J.; Baran, Phil S.
  Nature Chemical Biology (2007), 3 (7), 396-407CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  A review with refs. Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral, carbocyclic skeletons. Further oxidn. and rearrangement results in an almost endless no. of conceivable structures. The enormous structural diversity presented by this class of natural products ensures a broad range of biol. properties-ranging from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on synthetic strategies directed toward some of the most complex, biol. relevant terpenes prepd. by total synthesis within the past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct such natural products and the key chem. transformations and strategies that have been developed to meet these challenges.
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130. 130
  McKerrall, S. J.; Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5799– 5810 DOI: 10.1021/ja501881p
  130
  Development of a Concise Synthesis of (-)-Ingenol
  McKerrall, Steven J.; Joergensen, Lars; Kuttruff, Christian A.; Ungeheuer, Felix; Baran, Phil S.
  Journal of the American Chemical Society (2014), 136 (15), 5799-5810CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The complex diterpenoid (-)-ingenol (I) possesses a uniquely challenging scaffold and constitutes the core of a recently approved anti-cancer drug. This full account details the development of a short synthesis of I that takes place in two sep. phases (cyclase and oxidase) as loosely modeled after terpene biosynthesis. Initial model studies establishing the viability of a Pauson-Khand approach to building up the carbon framework are recounted. Extensive studies that led to the development of a 7-step cyclase phase to transform (+)-3-carene into a suitable tigliane-type core are also presented. A variety of competitive pinacol rearrangements and cyclization reactions were overcome to develop a 7-step oxidase phase producing (-)-ingenol. The pivotal pinacol rearrangement is further examd. through DFT calcns., and implications for the biosynthesis of (-)-ingenol are discussed.
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131. 131
  Michaudel, Q.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2015, 48, 712– 721 DOI: 10.1021/ar500424a
  There is no corresponding record for this reference.
132. 132
  Shah, S.; Ryan, C. J. Drugs Future 2009, 34, 873– 880 DOI: 10.1358/dof.2009.034.11.1441113
  132
  Abiraterone acetate: CYP17 inhibitor oncolytic
  Shah, S.; Ryan, C. J.
  Drugs of the Future (2009), 34 (11), 873-880CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
  A review. Androgen deprivation therapy has been the std. of care in advanced prostate cancer for over 50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone. The term castration-resistant prostate cancer (CRPC), however, is a misnomer, as the disease is still dependent on continued activation of the androgen receptor(AR). New secondary hormonal therapies seek to prolong suppression of the AR and thus delay the development of truly hormone-"refractory" prostate cancer. Extra-gonadal androgens, and specifically adrenal androgens, represent a means for continued AR-mediated growth in CRPC and have thus become a therapeutic target. Abiraterone acetate (CB-7630) is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from phase I and II trials suggest that prostate-specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large phase III clin. trials are currently open to accrual, and if abiraterone acetate is proven to be efficacious, it will result in widespread use of a drug specifically developed to suppress adrenal androgens.
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133. 133
  Doronina, S. O.; Mendelsohn, B. A.; Bovee, T. D.; Cerveny, C. G.; Alley, S. C.; Meyer, D. L.; Oflazoglu, E.; Toki, B. E.; Sanderson, R. J.; Zabinski, R. F.; Wahl, A. F.; Senter, P. D. Bioconjugate Chem. 2006, 17, 114– 124 DOI: 10.1021/bc0502917
  133
  Enhanced Activity of Monomethylauristatin F through Monoclonal Antibody Delivery: Effects of Linker Technology on Efficacy and Toxicity
  Doronina, Svetlana O.; Mendelsohn, Brian A.; Bovee, Tim D.; Cerveny, Charles G.; Alley, Stephen C.; Meyer, Damon L.; Oflazoglu, Ezogelin; Toki, Brian E.; Sanderson, Russell J.; Zabinski, Roger F.; Wahl, Alan F.; Senter, Peter D.
  Bioconjugate Chemistry (2006), 17 (1), 114-124CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
  We have previously shown that antibody-drug conjugates (ADCs) consisting of cAC10 (anti-CD30) linked to the antimitotic agent monomethylauristatin E (MMAE) lead to potent in vitro and in vivo activities against antigen pos. tumor models. MMAF is a new antimitotic auristatin deriv. with a charged C-terminal phenylalanine residue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE, most likely due to impaired intracellular access. In vitro cytotoxicity studies indicated that mAb-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-MMAF (mAb-L1-MMAF) conjugates were >2200-fold more potent than free MMAF on a large panel of CD30 pos. hematol. cell lines. As with cAC10-L1-MMAE, the corresponding MMAF ADC induced cures and regressions of established xenograft tumors at well tolerated doses. To further optimize the ADC, several new linkers were generated in which various components within the L1 linker were either altered or deleted. One of the most promising linkers contained a noncleavable maleimidocaproyl (L4) spacer between the drug and the mAb. CAC10-L4-MMAF was approx. as potent in vitro as cAC10-L1-MMAF against a large panel of cell lines and was equally potent in vivo. Importantly, cAC10-L4-MMAF was tolerated at >3 times the MTD of cAC10-L1-MMAF. LCMS studies indicated that drug released from cAC10-L4-MMAF was the cysteine-L4-MMAF adduct, which likely arises from mAb degrdn. within the lysosomes of target cells. This new linker technol. appears to be ideally suited for drugs that are both relatively cell-impermeable and tolerant of substitution with amino acids. Thus, alterations of the linker have pronounced impacts on toxicity and lead to new ADCs with greatly improved therapeutic indexes.
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134. 134
  Smaglo, B. G.; Aldeghaither, D.; Weiner, L. M. Nat. Rev. Clin. Oncol. 2014, 11, 637– 648 DOI: 10.1038/nrclinonc.2014.159
  134
  The development of immunoconjugates for targeted cancer therapy
  Smaglo, Brandon G.; Aldeghaither, Dalal; Weiner, Louis M.
  Nature Reviews Clinical Oncology (2014), 11 (11), 637-648CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)
  A review. Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three sep. components: an antibody that binds to a cancer cell antigen with high specificity, an effector mol. that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not sep. from the antibody during transit and will reliably release the effector to the cancer cell or tumor stroma. The high affinity antibody-antigen interaction allows specific and selective delivery of a range of effectors, including pharmacol. agents, radioisotopes, and toxins, to cancer cells. Some anticancer mols. are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.
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135. 135
  Tzogani, K.; Straube, M.; Hoppe, U.; Kiely, P.; O’Dea, G.; Enzmann, H.; Salmon, P.; Salmonson, T.; Pignatti, F. J. Dermatol. Treat. 2014, 25, 371– 374 DOI: 10.3109/09546634.2013.789474
  135
  The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use
  Tzogani, Kyriaki; Straube, Myrjam; Hoppe, Ute; Kiely, Peter; O'Dea, Geraldine; Enzmann, Harald; Salmon, Patrick; Salmonson, Tomas; Pignatti, Francesco
  Journal of Dermatological Treatment (2014), 25 (5), 371-374CODEN: JDTREY; ISSN:0954-6634. (Informa Healthcare)
  A review. The European Commission has recently issued a marketing authorisation valid throughout the European Union for 5-aminolaevulinic acid (Ameluz). The decision was based on the favorable opinion of the CHMP recommending a marketing authorization for 5-aminolaevulinic acid for treatment of actinic keratosis of mild to moderate intensity on the face and scalp. The active substance is a sensitizer used in photodynamic/radiation therapy (ATC code L01XD04). The gel should cover the lesions and approx. 5 mm of the surrounding area with a film of about 1 mm thickness. The entire treatment area should be illuminated with a red light source, either with a narrow spectrum around 630 nm and a light dose of approx. 37 J/cm2 or a broader and continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and 200 J/cm2. One session of photodynamic therapy should be administered for single or multiple lesions. Non- or partially responding lesions should be retreated in a second session 3 mo after the first treatment. 5-Aminolaevulinic acid is metabolized to protoporphyrin IX, a photoactive compd. which accumulates intracellularly in the treated actinic keratosis lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed which causes damage of cellular components and eventually destroys the target cells. The benefit with 5-aminolaevulinic acid is its ability to improve the complete response rate of actinic keratosis lesions. The most common side effects are reactions at the site of application. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the EMA website ().
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136. 136
  Teicher, B. A.; Tomaszewski, J. E. Biochem. Pharmacol. 2015, 96, 1– 9 DOI: 10.1016/j.bcp.2015.04.008
  There is no corresponding record for this reference.
137. 137
  Kim, K. B.; Crews, C. M. Nat. Prod. Rep. 2013, 30, 600– 604 DOI: 10.1039/c3np20126k
  137
  From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes
  Kim, Kyung Bo; Crews, Craig M.
  Natural Product Reports (2013), 30 (5), 600-604CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. Covering: 1992 to 2012The initial enthusiasm following the discovery of a pharmacol. active natural product is often fleeting due to the poor prospects for its ultimate clin. application. Despite this, the ever-changing landscape of modern biol. has a const. need for mol. probes that can aid in our understanding of biol. processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin's pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compd. of carfilzomib (Kyprolis®), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.
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138. 138
  Kuemler, I.; Mortensen, C. E.; Nielsen, D. L. Drugs Future 2011, 36, 825– 832 DOI: 10.1358/dof.2011.036.11.1711891
  138
  Trastuzumab emtansine: tumor-activated prodrug (TAP) immunoconjugate oncolytic
  Kuemler, I.; Mortensen, C. Ehlers; Nielsen, D. L.
  Drugs of the Future (2011), 36 (11), 825-832CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
  A review. Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate. The conjugate is comprised of the antibody trastuzumab, which is directed against the receptor tyrosine-protein kinase erbB-2 (HER2), a deriv. of the cytostatic agent maytansinoid DM1 (mertansine), and a linker that covalently binds these components together. Preclinically, trastuzumab emtansine has shown significant antitumor activity in HER2-pos. breast cancer cell lines and xenografts, including those resistant to trastuzumab or lapatinib. The pharmacokinetic profile is predictable, with minimal systemic exposure to free DM1. Phase I and II studies have demonstrated manageable toxicity. Phase II studies of trastuzumab emtansine monotherapy have shown response rates of 25-35% in patients with metastatic breast cancer who had previously received trastuzumab. Several combination regimens are under investigation. Phase III studies will help to define the role of trastuzumab emtansine within current treatment strategies.
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139. 139
  Ansell, S. M. Expert Opin. Invest. Drugs 2011, 20, 99– 105 DOI: 10.1517/13543784.2011.542147
  There is no corresponding record for this reference.
140. 140
  Péan, E.; Flores, B.; Hudson, I.; Sjöberg, J.; Dunder, K.; Salmonson, T.; Gisselbrecht, C.; Laane, E.; Pignatti, F. Oncologist 2013, 18, 625– 633 DOI: 10.1634/theoncologist.2013-0020
  There is no corresponding record for this reference.
141. 141
  Yano, S.; Kazuno, H.; Sato, T.; Suzuki, N.; Emura, T.; Wierzba, K.; Yamashita, J.; Tada, Y.; Yamada, Y.; Fukushima, M.; Asao, T. Bioorg. Med. Chem. 2004, 12, 3443– 3450 DOI: 10.1016/j.bmc.2004.04.046
  There is no corresponding record for this reference.
142. 142
  Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.; Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li, S. Y.; Chen, X. H.; Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.; Justice, R.; Farrell, A. T.; Pazdur, R. Clin. Cancer Res. 2015, 21, 2666– 2670 DOI: 10.1158/1078-0432.CCR-14-3119
  142
  FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma
  Lee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.; Ricci, M. Stacey; Saber, Haleh; Habtemariam, Bahru A.; Bullock, Julie; Bloomquist, Erik; Shen, Yuan Li; Chen, Xiao-Hong; Brown, Janice; Mehrotra, Nitin; Dorff, Sarah; Charlab, Rosane; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, Richard
  Clinical Cancer Research (2015), 21 (12), 2666-2670CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered i.v. at a dose of 1000 mg/m2 over 30 min once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiol. readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathol. Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), resp. The median duration of response, the key secondary efficacy endpoint, was 8.4 mo (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. Clin Cancer Res; 21(12); 2666-70. ©2015 AACR.
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143. 143
  Thorkildsen, C.; Neve, S.; Larsen, B. J.; Meier, E.; Petersen, J. S. J. Pharmacol. Exp. Ther. 2003, 307, 490– 496 DOI: 10.1124/jpet.103.051987
  143
  Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice
  Thorkildsen, Christian; Neve, Soren; Larsen, Bjarne Due; Meier, Eddi; Petersen, Jorgen Soberg
  Journal of Pharmacology and Experimental Therapeutics (2003), 307 (2), 490-496CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
  We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated Hb (HbA1C) from 8.4±0.4% (vehicle) to a min. of 6.2±0.3% (100 nmol/kg b.i.d.; p < 0.05 vs. vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was assocd. with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves β-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.
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144. 144
  Wang, Y.; Serradell, N.; Rosa, E.; Castaner, R. Drugs Future 2008, 33, 473– 477 DOI: 10.1358/dof.2008.033.06.1215244
  144
  BI-1356: Dipeptidyl-peptidase IV inhibitor antidiabetic agent
  Wang, Y.
  Drugs of the Future (2008), 33 (6), 473-477CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
  A review. BI-1356 is a dipeptidyl-peptidase IV (DPP IV, or CD26) inhibitor developed at Boehringer Ingelheim for the treatment of type 2 diabetes. BI-1356 demonstrated long-lasting DPP IV inhibition both in vitro and in vivo. In vitro, BI-1356 was at least 10,000-fold more selective for DPP IV than for DPP-8 and DPP-9. High potency and long-lasting inhibitory effects were also obsd. in vivo in mice and rats, the inhibition induced by BI-1356 being longer lasting than that induced by any other DPP IV inhibitor tested. BI-1356 exhibited nonlinear pharmacokinetics in healthy volunteers and patients with type 2 diabetes. Oral BI-1356 administered once daily proved to be well tolerated in healthy volunteers and patients with type 2 diabetes. Treatment with BI-1356 increased concns. of GLP-1 and reduced concns. of glucose in patients with type 2 diabetes, and it also significantly reduced Hb1Ac in diabetic patients. Phase III clin. trials are under way.
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145. 145
  Yoshida, T.; Akahoshi, F.; Sakashita, H.; Kitajima, H.; Nakamura, M.; Sonda, S.; Takeuchi, M.; Tanaka, Y.; Ueda, N.; Sekiguchi, S.; Ishige, T.; Shima, K.; Nabeno, M.; Abe, Y.; Anabuki, J.; Soejima, A.; Yoshida, K.; Takashina, Y.; Ishii, S.; Kiuchi, S.; Fukuda, S.; Tsutsumiuchi, R.; Kosaka, K.; Murozono, T.; Nakamaru, Y.; Utsumi, H.; Masutomi, N.; Kishida, H.; Miyaguchi, I.; Hayashi, Y. Bioorg. Med. Chem. 2012, 20, 5705– 5719 DOI: 10.1016/j.bmc.2012.08.012
  There is no corresponding record for this reference.
146. 146
  Kato, N.; Oka, M.; Murase, T.; Yoshida, M.; Sakairi, M.; Yamashita, S.; Yasuda, Y.; Yoshikawa, A.; Hayashi, Y.; Makino, M.; Takeda, M.; Mirensha, Y.; Kakigami, T. Bioorg. Med. Chem. 2011, 19, 7221– 7227 DOI: 10.1016/j.bmc.2011.09.043
  There is no corresponding record for this reference.
147. 147
  Cole, P.; Vicente, M.; Castañer, R. Drugs Future 2008, 33, 745– 751 DOI: 10.1358/dof.2008.033.09.1251351
  147
  Dapagliflozin: SGLT2 inhibitor antidiabetic agent
  Cole, P.; Vicente, M.; Castaner, R.
  Drugs of the Future (2008), 33 (9), 745-751CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
  A review. Diabetes is a growing epidemic for which new treatments are needed as it is often not controlled with current therapies. One potential means of treating diabetes is via modulation of glucose uptake. A novel strategy for achieving this is through inhibition of sodium-dependent glucose transporters (SGLTs), which mediate the process by which plasma glucose filtered in the kidney glomerulus is reabsorbed. The great majority of this process of reabsorption is mediated by SGLT2 and SGLT2 inhibitors have therefore been sought and identified in order to prevent renal glucose reabsorption and increase glucose excretion in urine. The compd. that has advanced the furthest is dapagliflozin, which demonstrated superior metabolic stability compared to early agents. Dapagliflozin also exhibited potent inhibition of SGLT2 and selectivity over SGLT1 in vitro, and was assocd. with reduced plasma glucose levels in animal models of diabetes after acute and chronic dosing. Dapagliflozin has proven safe and well tolerated in humans, with pharmacokinetic and pharmacodynamic variables indicating that daily dosing is appropriate. Double-blind trials in patients with type 2 diabetes revealed redns. in fasting and postprandial glucose, as well as significant redns. in HbA1c. Dapagliflozin has entered phase III evaluation.
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148. 148
  Chao, E. C. Drugs Future 2011, 36, 351– 357 DOI: 10.1358/dof.2011.036.05.1590789
  148
  Sodium/glucose cotransporter 2 inhibitor treatment of type 2 diabetes treatment of obesity
  Chao, Edward C.
  Drugs of the Future (2011), 36 (5), 351-357CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)
  A review. Sodium/glucose cotransporters (SGLTs) serve a crit. role in the reclamation of glucose in the kidney. Blocking this reabsorption, and thus increasing the amt. of glucose excretion, has been proposed as a novel strategy for treating diabetes. Canagliflozin is a C-glucoside with a thiophene ring that acts as a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although further data from multiple ongoing phase III clin. trials of canagliflozin and other SGLT2 inhibitors are forthcoming, results to date suggest that the benefits of SGLT2 inhibition may be achieved without causing significant adverse effects. This review will provide a description of the role of the kidney in glucose homeostasis and summarize the preclin. and clin. studies published thus far on canagliflozin.
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149. 149
  White, J. R., Jr. Ann. Pharmacother. 2015, 49, 582– 598 DOI: 10.1177/1060028015573564
  There is no corresponding record for this reference.
150. 150
  Imamura, M.; Nakanishi, K.; Suzuki, T.; Ikegai, K.; Shiraki, R.; Ogiyama, T.; Murakami, T.; Kurosaki, E.; Noda, A.; Kobayashi, Y.; Yokota, M.; Koide, T.; Kosakai, K.; Ohkura, Y.; Takeuchi, M.; Tomiyama, H.; Ohta, M. Bioorg. Med. Chem. 2012, 20, 3263– 3279 DOI: 10.1016/j.bmc.2012.03.051
  150
  Discovery of Ipragliflozin (ASP1941): A novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus
  Imamura, Masakazu; Nakanishi, Keita; Suzuki, Takayuki; Ikegai, Kazuhiro; Shiraki, Ryota; Ogiyama, Takashi; Murakami, Takeshi; Kurosaki, Eiji; Noda, Atsushi; Kobayashi, Yoshinori; Yokota, Masayuki; Koide, Tomokazu; Kosakai, Kazuhiro; Ohkura, Yasufumi; Takeuchi, Makoto; Tomiyama, Hiroshi; Ohta, Mitsuaki
  Bioorganic & Medicinal Chemistry (2012), 20 (10), 3263-3279CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  A series of C-glucosides with various heteroaroms. has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compds., the benzothiophene deriv. I (R =H) was found to have potent inhibitory activity against SGLT2 and good selectivity vs. SGLT1. Through further optimization of 14a, a novel benzothiophene deriv. I (R = F) (ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-Ay mice and STZ rats.
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151. 151
  Tiwari, A. Drugs Future 2012, 37, 637– 643 DOI: 10.1358/dof.2012.037.09.1848191
  151
  Luseogliflozin: SGLT2 inhibitor treatment of diabetes
  Tiwari, A.
  Drugs of the Future (2012), 37 (9), 637-643CODEN: DRFUD4; ISSN:0377-8282. (Thomson Reuters)
  A review. Luseogliflozin (TS-071), developed by Taisho Pharmaceutical, is a novel, potent sodium/glucose cotransporter 2 (SGLT2) inhibitor for the potential treatment of type 2 diabetes (T2D) and type 1 diabetes (T1D). Luseogliflozin exhibits high selectivity for SGLT2 over SGLT1 and the glucose transporters GLUT2 and GLUT4, with favorable pharmacokinetic and pharmacodynamic properties. Luseogliflozin exhibited increased urinary glucose excretion, with improved glucose tolerance and a significant redn. in fasting plasma glucose arid postprandial plasma glucose, with body wt. loss after chronic treatment in different animal models of diabetes and without an increase in plasma insulin. Clin. data in Japanese patients demonstrated that luseogliflozin was orally bioavailable, with a prolonged half-life, suitability for once-daily dosing and effective in significantly reducing glycated Hb and fasting plasma glucose, with body wt. loss. Luseogliflozin was well tolerated, without the risk of hypoglycemia and clin. meaningful changes in urinary vol., electrolyte excretion and renal function. The results from phase III clin. trials in T2D and T1D patients will be pivotal; however, the available data suggest that luseogliflozin has potential for success in this niche market segment.
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152. 152
  Poole, R. M.; Prossler, J. E. Drugs 2014, 74, 939– 944 DOI: 10.1007/s40265-014-0229-1
  There is no corresponding record for this reference.
153. 153
  Wilson, M. C.; Mori, T.; Rückert, C.; Uria, A. R.; Helf, M. J.; Takada, K.; Gernert, C.; Steffens, U. A. E.; Heycke, N.; Schmitt, S.; Rinke, C.; Helfrich, E. J. N.; Brachmann, A. O.; Gurgui, C.; Wakimoto, T.; Kracht, M.; Crüsemann, M.; Hentschel, U.; Abe, I.; Matsunaga, S.; Kalinowski, J.; Takeyama, H.; Piel, J. Nature 2014, 506, 58– 62 DOI: 10.1038/nature12959
  153
  An environmental bacterial taxon with a large and distinct metabolic repertoire
  Wilson, Micheal C.; Mori, Tetsushi; Rueckert, Christian; Uria, Agustinus R.; Helf, Maximilian J.; Takada, Kentaro; Gernert, Christine; Steffens, Ursula A. E.; Heycke, Nina; Schmitt, Susanne; Rinke, Christian; Helfrich, Eric J. N.; Brachmann, Alexander O.; Gurgui, Cristian; Wakimoto, Toshiyuki; Kracht, Matthias; Cruesemann, Max; Hentschel, Ute; Abe, Ikuro; Matsunaga, Shigeki; Kalinowski, Joern; Takeyama, Haruko; Piel, Joern
  Nature (London, United Kingdom) (2014), 506 (7486), 58-62CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Cultivated bacteria such as Actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa contg. talented bacteria indeed exist. Here, the authors report the single-cell- and metagenomics-based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chem. and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chem. uniqueness of 'Entotheonella' compds. provide significant opportunities for ecol. studies and drug discovery.
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154. 154
  Schofield, M. M.; Jain, S.; Porat, D.; Dick, G. J.; Sherman, D. H. Environ. Microbiol. 2015, 17, 3964– 3975 DOI: 10.1111/1462-2920.12908
  154
  Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743
  Schofield, Michael M.; Jain, Sunit; Porat, Daphne; Dick, Gregory J.; Sherman, David H.
  Environmental Microbiology (2015), 17 (10), 3964-3975CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
  Ecteinascidin 743 (ET-743, Yondelis) is a clin. approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anticancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the lab. using std. techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Anal. of the ∼631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome redn. Phylogenetic anal. suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 prodn. and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster's architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. Taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically important microorganism and highlight the wide diversity of bacteria capable of making potent natural products.
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155. 155
  Kusari, S.; Lamshöft, M.; Kusari, P.; Gottfried, S.; Zühlke, S.; Louven, K.; Hentschel, U.; Kayser, O.; Spiteller, M. J. Nat. Prod. 2014, 77, 2577– 2584 DOI: 10.1021/np500219a
  155
  Endophytes Are Hidden Producers of Maytansine in Putterlickia Roots
  Kusari, Souvik; Lamshoeft, Marc; Kusari, Parijat; Gottfried, Sebastian; Zuehlke, Sebastian; Louven, Kathrin; Hentschel, Ute; Kayser, Oliver; Spiteller, Michael
  Journal of Natural Products (2014), 77 (12), 2577-2584CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  Several recent studies have lent evidence to the fact that certain so-called plant metabolites are actually biosynthesized by assocd. microorganisms. In this work, we show that the original source organism(s) responsible for the biosynthesis of the important anticancer and cytotoxic compd. maytansine is the endophytic bacterial community harbored specifically within the roots of Putterlickia verrucosa and P. retrospinosa plants. Evaluation of the root endophytic community by chem. characterization of their fermn. products using HPLC-HRMSn, along with a selective microbiol. assay using the maytansine-sensitive type strain Hamigera avellanea revealed the endophytic prodn. of maytansine. This was further confirmed by the presence of AHBA synthase genes in the root endophytic communities. Finally, MALDI-imaging-HRMS was used to demonstrate that maytansine produced by the endophytes is typically accumulated mainly in the root cortex of both plants. Our study, thus, reveals that maytansine is actually a biosynthetic product of root-assocd. endophytic microorganisms. The knowledge gained from this study provides fundamental insights on the biosynthesis of so-called plant metabolites by endophytes residing in distinct ecol. niches.
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156. 156
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  Covering: 2000 to 2015While recent breakthroughs in the discovery of peptide antibiotics and other Peptidic Natural Products (PNPs) raise a challenge for developing new algorithms for their analyses, the computational technologies for high-throughput PNP discovery are still lacking. We discuss the computational bottlenecks in analyzing PNPs and review recent advances in genome mining, peptidogenomics, and spectral networks that are now enabling the discovery of new PNPs via mass spectrometry. We further describe the connections between these advances and the new generation of software tools for PNP dereplication, de novo sequencing, and identification.
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  Covering: up to 2015Over the centuries, microbial secondary metabolites have played a central role in the treatment of human diseases and have revolutionised the pharmaceutical industry. With the increasing no. of sequenced microbial genomes revealing a plethora of novel biosynthetic genes, natural product drug discovery is entering an exciting second golden age. Here, we provide a concise overview as an introductory guide to the main methods employed to unlock or up-regulate these so called 'cryptic', 'silent' and 'orphan' gene clusters, and increase the prodn. of the encoded natural product. With a predominant focus on bacterial natural products we will discuss the importance of the bioinformatics approach for genome mining, the use of first different and simple culturing techniques and then the application of genetic engineering to unlock the microbial treasure trove.
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  Natural Product Reports (2015), 32 (1), 29-48CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. Covering: up to Apr. 2014The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with scepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has re-bloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, with particular focus on natural products as promising starting points for antiviral lead development.
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  Natural Product Reports (2014), 31 (11), 1612-1661CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. Covering: 2008-2013. Previous review: 2008, 25, 475There are a significant no. of natural product (NP) drugs in development. We review the 100 NP and NP-derived compds. and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clin. trials or in registration at the end of 2013. 38 of these compds. and 33 ADCs are being investigated as potential oncol. treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurol. There was a spread of the NP and NP-derived compds. through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compds. were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compds. for which clin. trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analyzed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compds. in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clin. trials. The next few years will be crit. for NP-driven lead discovery, and a concerted effort is required to identify new biol. active pharmacophores and to progress these and existing compds. through pre-clin. drug development into clin. trials.
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  The 2015 Nobel Prize in Physiol. or Medicine recognized the advances made in treating neglected tropical diseases, using drugs whose origins lie in natural products.
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Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.5b01055.
- The drug data set (PDF)
- np5b01055_si_002.docx (189.16 kb)
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Natural Products as Sources of New Drugs from 1981 to 2014Click to copy article linkArticle link copied!

Journal of Natural Products

Abstract

SPECIAL ISSUE

Introduction

Chart 1

Results

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Figure 4

Major Categories of Sources

Subcategory

Figure 5

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Figure 7

Derivation of Oral Renin Inhibitors

Scheme 1

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Chart 2

Biologically Active Peptides

Modifications of Natural Products by Combinatorial Methods

Overview of Results

De Novo Combinatorial Drugs

Natural Product Mimics

Disease Area Breakdowns

Anti-infectives in General

Anitbacterial Agents

Chart 3

Antifungal Agents

Antiviral Drugs

Chart 4

Chart 5

Disease Areas without Current Natural Product Drugs

Disease Areas with “*/NM” Classified Drugs

Anticancer Drugs 1981–2014

Chart 6

Anticancer Drugs, Late 1930s to 2014

Small-Molecule Antidiabetic Drugs

Discussion

Increases in Biologicals and Vaccines from 2007

Potential Sources of Natural Product Skeletons

Genomic Sources of Novel NP Skeletons

Supporting Information

Terms & Conditions

Author Information

References

Cited By

Journal of Natural Products

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Abstract

Chart 1

Figure 1

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Figure 5

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Figure 7

Scheme 1

Figure 8

Figure 9

Figure 10

Figure 11

Chart 2

Chart 3

Chart 4

Chart 5

Chart 6

References

Supporting Information

Supporting Information

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Natural Products as Sources of New Drugs from 1981 to 2014
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