Perspectives
Druggability Assessment of Targets Used in Kinetic Target-Guided Synthesis
Miniperspective
M. Yagiz Unver - ,
Robin M. Gierse - ,
Harry Ritchie - , and
Anna K. H. Hirsch *
Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biological target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biological target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, we performed a druggability assessment for each target family reported in KTGS, calculated the pocket properties, and used them to extract possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall we conclude that the KTGS approach is universal and could be used without restrictions regarding the physicochemical properties of the addressed pocket.
Medicinal Chemistry and Use of Myosin II Inhibitor (S)-Blebbistatin and Its Derivatives
Bart I. Roman *- ,
Sigrid Verhasselt - , and
Christian V. Stevens *
(S)-Blebbistatin, a chiral tetrahydropyrroloquinolinone, is a widely used and well-characterized ATPase inhibitor selective for myosin II. The central role of myosin II in many normal and pathological biological processes has been revealed with the aid of this small molecule. The first part of this manuscript provides a summary of myosin II and (S)-blebbistatin literature from a medicinal chemist’s perspective. The second part of this perspective deals with the physicochemical deficiencies that trouble the use of (S)-blebbistatin in advanced biological settings: low potency and solubility, fluorescence interference, (photo)toxicity, and stability issues. A large toolbox of analogues has been developed in which particular shortcomings have been addressed. This perspective provides a necessary overview of these developments and presents guidelines for selecting the best available analogue for a given application. As the unmet need for high-potency analogues remains, we also propose starting points for medicinal chemists in search of nanomolar myosin II inhibitors.
Protein Arginine Methyltransferase 5 (PRMT5) as an Anticancer Target and Its Inhibitor Discovery
Yuanxiang Wang *- ,
Wenhao Hu - , and
Yanqiu Yuan *
PRMT5 is a major enzyme responsible for symmetric dimethylation of arginine residues on both histone and non-histone proteins, regulating many biological pathways in mammalian cells. PRMT5 has been suggested as a therapeutic target in a variety of diseases including infectious disease, heart disease, and cancer. Many PRMT5 inhibitors have been discovered in the past 5 years, and one entered clinical trial in 2015 for the treatment of solid tumor and mantle cell lymphoma (MCL). The aim of this review is to summarize the current understanding of the roles of PRMT5 in cancer and the discovery of PRMT5 enzymatic inhibitors. By reviewing the structure–activity relationship (SAR) of known inhibitors of PRMT5, we hope to provide guidance for future drug designs and inhibitor optimization. Opportunities and limitations of PRMT5 inhibitors for the treatment of cancer are also discussed.
Where Do Recent Small Molecule Clinical Development Candidates Come From?
Dean G. Brown *- and
Jonas Boström
An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = −0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.
Viewpoint
Cyclophilin Succumbs to a Macrocyclic Chameleon
Bradley C. Doak - and
Jan Kihlberg *
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Targets that have large and groove-shaped binding sites, such as cyclophilin, are difficult to drug with small molecules. Macrocycles of natural product origin can be ideal starting points for such targets as illustrated by the transformation of sanglifehrin A into an orally bioavailable potential candidate drug. Optimization benefits from development of convergent, modular synthetic routes in combination with structure and property based methods for lead optimization.
Featured Article
Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle
Richard L. Mackman *- ,
Victoria A. Steadman - ,
David K. Dean - ,
Petr Jansa - ,
Karine G. Poullennec - ,
Todd Appleby - ,
Carol Austin - ,
Caroline A. Blakemore - ,
Ruby Cai - ,
Carina Cannizzaro - ,
Gregory Chin - ,
Jean-Yves C. Chiva - ,
Neil A. Dunbar - ,
Hans Fliri - ,
Adrian J. Highton - ,
Hon Hui - ,
Mingzhe Ji - ,
Haolun Jin - ,
Kapil Karki - ,
Andrew J. Keats - ,
Linos Lazarides - ,
Yu-Jen Lee - ,
Albert Liclican - ,
Michael Mish - ,
Bernard Murray - ,
Simon B. Pettit - ,
Peter Pyun - ,
Michael Sangi - ,
Rex Santos - ,
Jonathan Sanvoisin - ,
Uli Schmitz - ,
Adam Schrier - ,
Dustin Siegel - ,
David Sperandio - ,
George Stepan - ,
Yang Tian - ,
Gregory M. Watt - ,
Hai Yang - , and
Brian E. Schultz
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Articles
Discovery of Tarantula Venom-Derived NaV1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis
Bin Wu *- ,
Justin K. Murray - ,
Kristin L. Andrews - ,
Kelvin Sham - ,
Jason Long - ,
Jennifer Aral - ,
Joseph Ligutti - ,
Shanti Amagasu - ,
Dong Liu - ,
Anruo Zou - ,
Xiaoshan Min - ,
Zhulun Wang - ,
Christopher P. Ilch - ,
Thomas J. Kornecook - ,
Min-Hwa Jasmine Lin - ,
Xuhai Be - ,
Les P. Miranda - ,
Bryan D. Moyer - , and
Kaustav Biswas *
Inhibitors of the voltage-gated sodium channel NaV1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified NaV1.7-inhibitory peptides GpTx-1 and JzTx-V from tarantula venom screens. Potency and selectivity were modulated through attribute-based positional scans of native residues via chemical synthesis. Herein, we report JzTx-V lead optimization to identify a pharmacodynamically active peptide variant. Molecular docking of peptide ensembles from NMR into a homology model-derived NaV1.7 structure supported prioritization of key residues clustered on a hydrophobic face of the disulfide-rich folded peptide for derivatization. Replacing Trp24 with 5-Br-Trp24 identified lead peptides with activity in electrophysiology assays in engineered and neuronal cells. 5-Br-Trp24 containing peptide AM-6120 was characterized in X-ray crystallography and pharmacokinetic studies and blocked histamine-induced pruritis in mice after subcutaneous administration, demonstrating systemic NaV1.7-dependent pharmacodynamics. Our data suggests a need for high target coverage based on plasma exposure for impacting in vivo end points with selectivity-optimized peptidic NaV1.7 inhibitors.
Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis
Fen Jiang - ,
An-ping Guo - ,
Jia-chen Xu - ,
Qi-Dong You *- , and
Xiao-Li Xu *
As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced “Phe199 shift” effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating “benzamide” moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.
Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
Anders Højgaard Hansen - ,
Eugenia Sergeev - ,
Daniele Bolognini - ,
Richard R. Sprenger - ,
Jeppe Hvidtfeldt Ekberg - ,
Christer S. Ejsing - ,
Christine J. McKenzie - ,
Elisabeth Rexen Ulven - ,
Graeme Milligan - , and
Trond Ulven *
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Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases
Montse Erra *- ,
Joan Taltavull - ,
Francisco Javier Bernal - ,
Juan Francisco Caturla - ,
Marta Carrascal - ,
Lluís Pagès - ,
Marta Mir - ,
Sònia Espinosa - ,
Jordi Gràcia - ,
María Domínguez - ,
Mar Sabaté - ,
Stéphane Paris - ,
Mónica Maldonado - ,
Begoña Hernández - ,
Mónica Bravo - ,
Elena Calama - ,
Montserrat Miralpeix - ,
Martin D. Lehner - , and
Marta Calbet
Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.
Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses
Thomas Szekely - ,
Olivier Roy - ,
Edith Dériaud - ,
Aurélie Job - ,
Richard Lo-Man - ,
Claude Leclerc *- , and
Claude Taillefumier *
We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a β-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323–339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.
Pathway-Based Drug Repositioning for Cancers: Computational Prediction and Experimental Validation
Michio Iwata - ,
Lisa Hirose - ,
Hiroshi Kohara - ,
Jiyuan Liao - ,
Ryusuke Sawada - ,
Sayaka Akiyoshi - ,
Kenzaburo Tani - , and
Yoshihiro Yamanishi *
Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use molecular pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chemically induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and experimentally validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
[99mTc][Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of αvβ3 Integrin: Synthesis, Structure–Activity and Pharmacokinetic Studies
Cristina Bolzati *- ,
Nicola Salvarese - ,
Debora Carpanese - ,
Roberta Seraglia - ,
Laura Meléndez-Alafort - ,
Antonio Rosato - ,
Domenica Capasso - ,
Michele Saviano - ,
Annarita Del Gatto - ,
Daniela Comegna - , and
Laura Zaccaro
New integrin-selective molecules suitable for therapeutic or imaging purposes are currently of interest in development of effective personalized medical platforms. RGDechi is a bifunctional peptide selective for integrin αvβ3. Herein, RGDechi and three truncated derivatives functionalized with a cysteine (1–4) were synthesized and labeled with the [99mTc][Tc(N)PNP43]-synthon ([PNP43 = (CH3)2P(CH2)2N(C2H4OCH3)(CH2)2P(CH3)2]) (99mTc1–4) as a basis for selective integrin recognition. The pharmacological parameters of all radiolabeled peptides were assessed along with the pharmacokinetic profiles of the most promising 99mTc1 and 99mTc2 compounds both on healthy and melanoma-bearing mice. Their metabolism and metabolite identification are also reported. 99mTc1–2 are able to discriminate between endogenously expressed integrins αvβ3 and αvβ5 and possess favorable pharmacokinetics characterized by low liver uptake and rapid elimination from nontarget tissues resulting in positive target-to-nontarget ratios. Results are encouraging; the presented construct can be considered the starting point for the development of agents for the selective detection of αvβ3 expression by SPECT.
Discovery of a Branched Peptide That Recognizes the Rev Response Element (RRE) RNA and Blocks HIV-1 Replication
Yumin Dai - ,
Jessica E. Wynn - ,
Ashley N. Peralta - ,
Chringma Sherpa - ,
Bhargavi Jayaraman - ,
Hao Li - ,
Astha Verma - ,
Alan D. Frankel - ,
Stuart F. Le Grice - , and
Webster L. Santos *
We synthesized and screened a unique 46 656-member library composed of unnatural amino acids that revealed several hits against RRE IIB RNA. Among the hit peptides identified, peptide 4A5 was found to be selective against competitor RNAs and inhibited HIV-1 Rev-RRE RNA interaction in cell culture in a p24 ELISA assay. Biophysical characterization in a ribonuclease protection assay suggested that 4A5 bound to the stem-loop region in RRE IIB while SHAPE MaP probing with 234 nt RRE RNA indicated additional interaction with secondary Rev binding sites. Taken together, our investigation suggests that HIV replication is inhibited by 4A5 blocking binding of Rev and subsequent multimerization.
Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists
Panfeng Peng - ,
Huan Chen - ,
Ya Zhu - ,
Zhilong Wang - ,
Jian Li - ,
Rong-Hua Luo - ,
Jiang Wang - ,
Liang Chen - ,
Liu-Meng Yang - ,
Hualiang Jiang - ,
Xin Xie - ,
Beili Wu *- ,
Yong-Tang Zheng *- , and
Hong Liu *
CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1–34) were synthesized, displaying CCR5-antagonist activities in the 2.3–296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 μM, which overcomes the potential drug–drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.
Evaluation of Novel Tumor-Targeted Near-Infrared Probe for Fluorescence-Guided Surgery of Cancer
Sakkarapalayam M. Mahalingam - ,
Sumith A. Kularatne *- ,
Carrie H. Myers - ,
Pravin Gagare - ,
Mohammad Norshi - ,
Xin Liu - ,
Sunil Singhal - , and
Philip S. Low *
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Because the most reliable therapy for cancer involves quantitative resection of all diseased tissue, considerable effort has been devoted to improving a surgeon’s ability to locate and remove all malignant lesions. With the aid of improved optical imaging equipment, we and others have focused on developing tumor-targeted fluorescent dyes to selectively illuminate cancer nodules during surgery. We describe here the design, synthesis, optical properties, in vitro and in vivo tumor specificity/affinity, pharmacokinetics, preclinical toxicology, and some clinical application of a folate receptor (FR)-targeted NIR dye (OTL38) that concentrates specifically in cancer tissues and clears rapidly from healthy tissues. We demonstrate that OTL38 binds FR-expressing cells with ∼1 nM affinity and eliminates from receptor negative tissues with a half-time of <30 min. We further show that OTL38 enables visualization of malignant lesions at concentrations less than 100-fold those required to elicit signs of toxicity. Since OTL38 also provides excellent tumor contrast in both murine tumor models and human cancer patients, we conclude that OTL38 constitutes an excellent NIR dye for fluorescence-guided resection of malignant lesions in cancer patients.
Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase
Ingrid Buchler - ,
Daniel Akuma - ,
Vinh Au - ,
Gregory Carr - ,
Pablo de León - ,
Michael DePasquale - ,
Glen Ernst - ,
Yifang Huang - ,
Martha Kimos - ,
Anna Kolobova - ,
Michael Poslusney - ,
Huijun Wei - ,
Dominique Swinnen - ,
Florian Montel - ,
Florence Moureau - ,
Emilie Jigorel - ,
Monika-Sarah E. D. Schulze - ,
Martyn Wood - , and
James C. Barrow *
A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.
Synthesis, Receptor Affinity, and Antiallodynic Activity of Spirocyclic σ Receptor Ligands with Exocyclic Amino Moiety
Melanie Bergkemper - ,
Elisabeth Kronenberg - ,
Simone Thum - ,
Frederik Börgel - ,
Constantin Daniliuc - ,
Dirk Schepmann - ,
Francisco Rafael Nieto - ,
Peter Brust - ,
Raquel F. Reinoso - ,
Inés Alvarez - , and
Bernhard Wünsch *
In order to detect novel σ receptor ligands, the rigid spiro[[2]benzopyran-1,1′-cyclohexan]-4′-one was connected with amino moieties derived from σ2 receptor preferring lead compounds resulting in mixtures of trans- and cis-configured amines 6, 18, and 27. In a four step synthesis the methyl acetals 6 were converted into fluoroethyl derivatives 13 and 30. The most promising σ2 receptor ligand is the methyl acetal 6a bearing a 2,4-dimethylbenzylamino moiety. The fluoroethyl derivatives 13c and 13d reveal high σ1 affinity but moderate selectivity over the σ2 subtype. In mice 13c and 13d showed antiallodynic activity that is stronger than that of the reference σ1 antagonist BD-1063 (34). Since the antiallodynic activity of 13c could only be partially reversed by the σ1 agonist PRE-084 (35), it is postulated that a second mechanism contributes to its overall antiallodynic effect. In contrast, the antiallodynic effect of its diastereomer 13d can be totally explained by a σ1 antagonism.
Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385)
Paul M. Wehn *- ,
James P. Rizzi - ,
Darryl D. Dixon - ,
Jonas A. Grina - ,
Stephen T. Schlachter - ,
Bin Wang - ,
Rui Xu - ,
Hanbiao Yang - ,
Xinlin Du - ,
Guangzhou Han - ,
Keshi Wang - ,
Zhaodan Cao - ,
Tzuling Cheng - ,
Robert M. Czerwinski - ,
Barry S. Goggin - ,
Heli Huang - ,
Megan M. Halfmann - ,
Melissa A. Maddie - ,
Emily L. Morton - ,
Sarah R. Olive - ,
Huiling Tan - ,
Shanhai Xie - ,
Tai Wong - ,
John A. Josey - , and
Eli M. Wallace
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel–Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X-ray Structural Studies
Arun K. Ghosh *- ,
Jacqueline N. Williams - ,
Rachel Y. Ho - ,
Hannah M. Simpson - ,
Shin-ichiro Hattori - ,
Hironori Hayashi - ,
Johnson Agniswamy - ,
Yuan-Fang Wang - ,
Irene T. Weber - , and
Hiroaki Mitsuya
We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.
Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4)
Edward J. Brnardic *- ,
Guosen Ye - ,
Carl Brooks - ,
Carla Donatelli - ,
Linda Barton - ,
Jeff McAtee - ,
Robert M. Sanchez - ,
Arthur Shu - ,
Karl Erhard - ,
Lamont Terrell - ,
Grazyna Graczyk-Millbrandt - ,
Yanan He - ,
Melissa H. Costell - ,
David J. Behm - ,
Theresa Roethke - ,
Patrick Stoy - ,
Dennis A. Holt - , and
Brian G. Lawhorn
A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure–activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis
Beatrice Riva - ,
Alessia Griglio - ,
Marta Serafini - ,
Celia Cordero-Sanchez - ,
Silvio Aprile - ,
Rosanna Di Paola - ,
Enrico Gugliandolo - ,
Dalia Alansary - ,
Isabella Biocotino - ,
Dmitry Lim - ,
Giorgio Grosa - ,
Ubaldina Galli - ,
Barbara Niemeyer - ,
Giovanni Sorba - ,
Pier Luigi Canonico - ,
Salvatore Cuzzocrea - ,
Armando A. Genazzani - , and
Tracey Pirali *
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.
Brief Articles
Biodegradable Amphipathic Peptide Hydrogels as Extended-Release System for Opioid Peptides
Charlotte Martin - ,
Maria Dumitrascuta - ,
Morgane Mannes - ,
Aquilino Lantero - ,
Dominik Bucher - ,
Katja Walker - ,
Yannick Van Wanseele - ,
Edith Oyen - ,
Sophie Hernot - ,
Ann Van Eeckhaut - ,
Annemieke Madder *- ,
Richard Hoogenboom *- ,
Mariana Spetea *- , and
Steven Ballet *
Chronic pain is currently treated with opioids that offer unsatisfactory long-term analgesia and produce serious side effects. There is a clear need for alternative therapies. Herein, peptide-based hydrogels are used as extended-release drug delivery carriers. Two different formulations were developed: the drug is coformulated within the hydrogel; the drug is an integral part of the hydrogelator. Both strategies afford a prolonged and significant antinociception up to 72 h after subcutaneous administration in mice.
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