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Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase
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  • Annachiara Tinivella
    Annachiara Tinivella
    Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
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  • Marta Banchi
    Marta Banchi
    Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
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  • Guido Gambacorta
    Guido Gambacorta
    Department of Chemistry, University of Durham, Lower Mount Joy, South Rd, Durham DH1 3LE, U.K.
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  • Federica Borghi
    Federica Borghi
    Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
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  • Paola Orlandi
    Paola Orlandi
    Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
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  • Ian R. Baxendale
    Ian R. Baxendale
    Department of Chemistry, University of Durham, Lower Mount Joy, South Rd, Durham DH1 3LE, U.K.
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    Orcidhttps://orcid.org/0000-0003-1297-1552
  • Antonello Di Paolo
    Antonello Di Paolo
    Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
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  • Guido Bocci
    Guido Bocci
    Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
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  • Luca Pinzi*
    Luca Pinzi
    Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
    *Email: [email protected]. Tel.: +39 059 2058625.
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    Orcidhttps://orcid.org/0000-0001-5572-2121
  • Giulio Rastelli*
    Giulio Rastelli
    Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
    *Email: [email protected]. Tel.: +39 059 2058564.
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    Orcidhttps://orcid.org/0000-0002-2474-0607
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ACS Pharmacology & Translational Science

Cite this: ACS Pharmacol. Transl. Sci. 2023, 6, 12, 1870–1883
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https://doi.org/10.1021/acsptsci.3c00183
Published November 23, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.

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Subjects

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Nowadays, breast cancer (BC) is the most-commonly diagnosed malignant cancer in women, accounting for 36% of oncological patients. (1,2) The incidence of BC is steadily increasing. Despite the progress in early diagnosis and treatment, which have improved survival rates, continued research into new therapies is still needed. (2) BC is classified as hormone receptor positive, (3,4) based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 positive (ERBB2/HER2+). (5) Approximately 70% of diagnosed BCs are ER+, and prolonged exposure to hormones is known to induce cancer. (4) ER+ patients are clinically treated with (i) selective estrogen receptor modulators (SERMs), such as tamoxifen; (ii) selective estrogen receptors degraders (SERDs); or (iii) aromatase inhibitors (AIs). AIs inhibit a key enzyme for the conversion of androgens to estrogens. (6,7) The 4-hydroxy metabolite of tamoxifen competitively binds to ER in BC cells, thereby inhibiting transcription and ensuing mitogenic effects in both pre- and postmenopausal women. (8,9) AIs suppress aromatase activity, thus, decreasing circulating estrogen levels and preventing BC cells from proliferation. AIs are usually employed as a second line of treatment in tamoxifen-resistant tumors and are effective only in postmenopausal women, who represent the majority of BC patients. (4) The discouraging risk/benefit profile of tamoxifen has prevented the use of this drug for periods longer than 5 years, and severe toxicities, including endometrial cancer and thrombosis, have been observed. (9) In contrast, AIs have shown better efficacy and tolerability in comparison with tamoxifen, thus becoming the first choice as adjuvant therapy for postmenopausal women. (8) Unfortunately, most patients who survive cancer die from other compromised health conditions, in particular cardiovascular diseases (CVDs). (10) Indeed, estrogens plays an important role in protecting the heart, preventing heart failure, post myocardial infarction and ventricular hypertrophy and remodeling, (11−14) while also preventing kidney issues. (15) The low estrogen levels typical of menopausal women are further reduced by treatment with AIs in BC patients, leading to major risks of CVDs. Long-term estrogen deficiency after AIs treatment also influences the physiological functions of estrogens and leads to changes in lipid profiles as well as bone loss. (16) Altered lipid profiles are a possible contributor to the increased risk of CVD in these patients, although this can be partially managed with antihyperlipidemic drugs. (17) In addition, low levels of estrogens negatively interfere with the Renin–Angiotensin–Aldosterone system (RAAS) by increasing the concentration of all components of the RAAS, especially aldosterone, because high levels of renin, angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and angiotensin type 1 receptor (AT1R) further stimulate aldosterone biosynthesis. (18−23) Aldosterone excess (hyperaldosteronism) leads to kidney, brain, blood vessel, and heart complications, (9) pointing to the need for maintaining balanced plasma aldosterone levels during estrogen deficiency. This effect can be achieved by inhibiting the aldosterone synthase enzyme (CYP11B2), which plays a key role in the biosynthesis of aldosterone by converting 11-deoxycorticosterone to aldosterone. (8,24)
Based on this rationale, this work aims at identifying dual inhibitors of the aromatase CYP19A1 and aldosterone synthase CYP11B2 enzymes as a straightforward way to provide an effective and safer cancer treatment while potentially reducing cardiovascular issues. Indeed, a polypharmacological approach may be more effective and can have several potential advantages over single-target or multiple-drug regimens. (25) To this end, a library of benzylimidazole compounds was synthesized and analyzed in silico by means of an integrated approach, which included: (i) focused polypharmacology searches made through the LigAdvisor web platform developed in our group; (26) (ii) 3D ligand-based similarity analyses; and (iii) docking calculations into selected conformations of the CYP19A1, CYP11B2 and CYP11B1 enzymes. The biological evaluation of the best candidates led to the identification of promising compound X21, which showed potent and balanced aromatase and aldosterone synthase dual inhibitory activity, high selectivity, promising cellular activity, and no cardiotoxicity, thus constituting an excellent candidate for further evaluation.

Results and Discussion

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Chemistry

Based on the chemical structure and mechanism of action of fadrozole (Figure 1), (27−31) which is a known CYP19A1 and CYP11B2 inhibitor that however lacks selectivity against CYP11B1, a library of benzylimidazole derivatives (Figure 2) was synthesized and thoroughly investigated.

Figure 1

Figure 1. Structures of (R)-fadrozole and (S)-fadrozole.

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Figure 2

Figure 2. Synthesized library of benzylimidazole derivatives.

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Figure 1 shows the enantiomers of fadrozole, which display different inhibitory activity. In particular, while (S)-fadrozole potently inhibits CYP19A1 and CYP11B1 and has lower activity on CYP11B2, (R)-fadrozole is scarcely active on CYP19A1 and potently inhibits both CYP11B2 and CYP11B1 with no selectivity. (32−34) This is an important aspect to emphasize in order to better evaluate the potential inhibitory activity of the benzylimidazole derivatives synthesized in this work (Figure 2). In fact, compounds showing unselective inhibition of CYP11B2 and CYP11B1 might provide severe side effects, progressing to acute adrenal insufficiency and potentially fatal cardiovascular collapse. (35) The compounds were synthesized using previously reported synthetic routes. (36−39) The functionalized thioimidazole species were assembled through a multicomponent one-pot process based upon a Marckwald reaction. (36) For example, compound X1 was synthesized starting from dihydroxyacetone dimer, potassium thiocyanate, and the appropriately functionalized 2,4-dichlorobenzylic amine hydrochloride salt. These thioimidazole derivatives (i.e., X1, X5, X10, and X19) were also derivatized, e.g., through: (i) alkylation/SNAr arylation of the nucleophilic thiol (39) (i.e., X9, X11–X18); (ii) thiol oxidative cleavage (37) (i.e., by desulfurization to yield an imidazole core to obtain X20, X21, and X24), and/or Corey–Gilman–Ganem oxidation of the primary alcohol side chain to obtain aldehydes or esters compounds X2, X3, X6–X8, and X23), or; (37) (iii) through activation and nucleophilic substitution as in the case of X22. Overall, the synthesized library consisted of 24 benzylimidazole derivatives (MW from 190 to 450 Da) variously decorated on the benzene and imidazole rings (Figure 2). Most of the compounds presented at least one substituent on the benzene ring, especially halogens. In these cases, one or two halogens are introduced at each position of the aromatic core. Regarding compounds X21 and X22, a nitrile group was located in para position to the methylene bridge, while derivatives X14 and X17 presented a thiophene and a 1,3-benzodioxolane ring, respectively. Substitutions on imidazole mainly involved positions 2- and 5-positions. The 2-position was substituted with a reactive thiol group (X1, X5, X10, X19) or a thioether, incorporating simple hydrocarbons (X18), or substituted aromatic rings (X9, X11–X17). The 5-position was functionalized with primary alcohols or esters. Exceptions were compounds X16 and X22, which presented an aldehyde and a substituted piperazine, respectively. Compound X4 was the only one of the series to possess an additional primary alcohol at position 4 of the imidazole. In conclusion, the library included molecules having a common substructure but a relatively wide diversity and MW range, owing to the various functional groups present on the benzylimidazole core. This library was analyzed through ligand-based and structure-based computational tools in order to identify the more promising candidates for dual inhibition.

Computational Analyses

In order to identify the best potential dual inhibitors of CYP19A1 and CYP11B2, the synthesized compounds were investigated in silico with LigAdvisor (https://ligadvisor.unimore.it/, accessed on July second, 2021) (26) a Web server developed in our group that facilitates polypharmacology and drug repurposing predictions. (25,40,41) In particular, LigAdvisor implements ECFP4 (circular–equivalent to Morgan) and MACCS fingerprints-based searches on DrugBank (42) and Protein Data Bank (PDB) (43) ligands, which are less populated by pan-assay interference and potential false-positive compounds. The performed 2D-similarity analyses highlighted a significant degree of similarity between compounds X21 and X12 with anastrozole (DB01217) and levoketoconazole (DB05667) (Table S1). Of note, anastrozole is a potent AI, while levoketoconazole shows significant activity against aromatase, CYP11B2 and CYP11B1. (44−48) Compounds X2, X3, X6, and X8 resulted to be similar to the highest number of DrugBank compounds with reported activity annotations on CYP19A1, CYP11B2, and CYP11B1 (Tables 1 and S1), whereas compounds X21 and X22 resulted to be similar to the highest number of PDB ligands according to ECFP4fp fingerprints (Tables 1 and S1). In particular, X21 resulted significantly similar to (S)-fadrozole (PDB ligand ID: JD7), (49) osilodrostat (PDB ligand ID: YSY), (50) and (R)-fadrozole (PDB ligand ID: 0T3), (51) which are potent inhibitors reported in crystallographic complexes with CYP11B1 and CYP11B2, respectively. Conversely, no significant ligand similarity was observed according to the MACCS fingerprints (data not shown).
Table 1. Number of Synthesized Compounds Showing Similarity Values Above Commonly Accepted Thresholds, (52) with Respect to Molecules with Activity Annotations on CYP19A1, CYP11B1, and CYP11B2a
compound IDCYP19ACYP11B1CYP11B2
N similar compounds based on ECFP4fpbN similar compounds based on TanimotoCombocN similar compounds based on ECFP4fpbN similar compounds based on TanimotoCombocN similar compounds based on ECFP4fpbN similar compounds based on TanimotoComboc
X10, 20, 0, 00, 20, 0, 41, 10, 0, 4
X20, 30, 0, 00, 30, 0, 153, 20, 0, 14
X30, 30, 0, 50, 30, 0, 243, 20, 0, 21
X40, 10, 0, 00, 10, 0, 00, 00, 0, 0
X50, 00, 0, 00, 10, 0, 40, 00, 0, 4
X60, 30, 0, 00, 30, 0, 173, 20, 0, 16
X70, 10, 0, 00, 10, 0, 30, 00, 0, 2
X80, 30, 0, 00, 20, 0, 71, 10, 0, 6
X90, 10, 0, 00, 00, 0, 00, 00, 0, 0
X100, 10, 0, 00, 00, 0, 10, 00, 0, 1
X110, 10, 0, 00, 10, 0, 00, 00, 0, 0
X120, 10, 0, 00, 10, 0, 00, 00, 0, 0
X130, 20, 0, 00, 10, 0, 02, 00, 0, 0
X140, 20, 0, 00, 10, 0, 00, 10, 0, 0
X150, 10, 0, 00, 10, 0, 00, 00, 0, 0
X160, 10, 0, 00, 00, 0, 00, 00, 0, 0
X170, 10, 0, 00, 10, 0, 00, 00, 0, 0
X180, 10, 0, 00, 10, 0, 30, 00, 0, 3
X190, 10, 0, 00, 10, 0, 30, 00, 0, 3
X200, 10, 0, 31, 10, 0, 202, 00, 0, 18
X210, 20, 0, 71, 11, 1, 153, 11, 1, 15
X220, 20, 0, 01, 20, 0, 05, 20, 0, 0
X230, 20, 0, 00, 10, 0, 30, 00, 0, 2
X240, 10, 0, 21, 10, 0, 92, 00, 0, 5
a

ECFP4fp-based similarity estimations were performed with the LigAdvisor Web server, (25) while 3D similarity estimations were made with the ROCS software. (53)

b

For each synthesized compound, the number of “PDB ligands, DrugBank ligands” that showed Tanimoto index above 0.3 is reported.

c

For each synthesized compound, the number of “PDB ligands, DrugBank ligands, ChEMBL ligands” that showed TanimotoCombo index above 1.5 is reported (only ChEMBL ligands with reported IC50, Ki, Kd, EC50, and potency below 1 μM were taken into consideration).

A series of 3D similarity evaluations with respect to ligands extracted from DrugBank, PDB, and ChEMBL (54,55) were also performed by using ROCS, as detailed in Methods section. 3D-similarity evaluations revealed that compound X21 was the only one to have a significant (TanimotoCombo index higher than 1.5) steric and electrostatic overlap with (S)-fadrozole (PDB ligand ID: JD7) (Figure 3a) and (R)-fadrozole (PDB ligand ID: 0T3), which have been cocrystallized with CYP11B2 (PDB ID: 6M7X) (49) and CYP11B1 (PDB ID: 4FDH), (51) respectively (Table S3). Notably, fadrozole has already been tested in vitro against CYP19A1, (56,57) CYP11B1, (32−34) and CYP11B2 (33) with good outcomes, supporting the selection of compound X21 as a valuable candidate for further evaluation. However, it should be pointed out that fadrozole lacks selectivity against CYP11B1. (32−34) Similar results arose from the 3D-similarity analyses against DrugBank compounds (Table S3), which allowed the identification of a notable degree of similarity between compound X21 and DB11837 (osilodrostat, PDB ligand ID: YSY) (Figure 3b), the latter compound being active against all investigated CYP19A1, CYP11B1, and CYP11B2 enzymes. (32,33) Finally, 3D similarities against ChEMBL ligands allowed the identification of four similar CYP19A1 inhibitors, 14 CYP11B1 inhibitors, and 14 CYP11B2 inhibitors (Table S2).

Figure 3

Figure 3. Predicted 3D ROCS-based alignments of compound X21 with (S)-fadrozole (a), osilodrostat (b), and CHEMBL162496 (c).

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Again, compound X21 emerged as the top-ranking candidate, being the only one to show a good overlap with aromatase ligands reported in ChEMBL (e.g., CHEMBL162496, IC50 of 15 nM) (28) (Figure 3c). Importantly, compound X21 was previously reported to be active against aldosterone synthase (CYP11B2, IC50 = 29 nM) and to be 10-fold less active against 11β-hydroxylase (CYP11B1, IC50 = 285 nM), (33) but to the best of our knowledge it was never tested against aromatase. The ligand-based analyses described above were complemented with structure-based analyses, e.g., docking into the binding sites of CYP19A1, CYP11B1, and CYP11B2 by means of FRED (OpenEye). (58) According to docking, only compounds X1 and X21 showed good complementarity with aromatase (Figure 4a,b), the predicted binding scores (Table S3) being better than those of (R)- and (S)-fadrozole.

Figure 4

Figure 4. Predicted binding mode of compounds X1 (a) and X21 (b) into the aromatase (CYP19A1) binding site.

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In the predicted docking poses (Figure 4), the hydroxyl group of the two compounds H-bonds with Asp309, while the imidazole nitrogen lone pair coordinates the Fe2+ ion of HEME, similarly to (R)- and (S)-fadrozole (Figure S1a,b). Moreover, compound X21 makes an additional hydrogen bond with the backbone of Met374 (Figure 4b), thus mimicking the H-bond established by the carbonyl group of androst-4-ene-3,17-dione (PDB ligand ID: ASD). (59) Docking calculations of X21 into the CYP11B1 binding site showed that the compound hydrogen bonds with the backbone atoms of Leu382 and Ala313, and coordinates the Fe2+ ion of HEME. A similar binding pose was obtained in CYP11B2; but in this case, the hydroxyl group of the ligand was not engaged in hydrogen bonds with active site residues (Figure S1d).

Biological Evaluation

In Vitro Inhibitory Activity

Standing on the results described above, compounds X1 and X21 emerged as the most promising compounds for biological testing. Hence, the two compounds were tested in vitro to assess their inhibitory activity against the recombinant aromatase enzyme, using letrozole as a reference (Table 2). (60)
Table 2. Inhibitory Activity of X21 (IC50, nM) against the CYP19A1 (Aromatase), CYP11B2 (Aldosterone Synthase), and CYP11B1 (11β-Hydroxylase) Enzymes
compoundIC50 (nM)CYP11B1/CYP11B2 selectivity ratio
CYP19A1CYP11B2CYP11B1
X212.329a285a9.8
(S)-fadrozole3.0–17b171c40c0.2
(R)-fadrozole680–6000d,e6.0c11c1.8
letrozole0.51420f2620f1.8
a

Note: ref (33).

b

Refs (56,57).

c

Refs (32−34).

d

Ref (56).

e

Ref (61).

f

Ref (60).

Unfortunately, compound X1 showed no inhibition of CYP19A1. To find an explanation, we hypothesized that the lack of activity could be due to the tautomeric equilibria of the thiol group present on the imidazole ring. Quantum mechanical calculations made with Jaguar (62) confirmed that the thioketone form was several kcals/mol more stable than the thiol form (data not shown). In the thioketone tautomer, the coordination of the Fe2+ of the HEME group by means of the imidazole nitrogen lone pair would be disrupted, thus explaining the observed lack of activity. Gratifyingly, compound X21 displayed potent nanomolar inhibitory activity of aromatase (CYP19A1, IC50 of 2.3 nM, Table 2), which adds to the already reported potent and selective inhibition of aldosterone synthase (CYP11B2, IC50 of 29 nM) (33) and 10-fold selectivity with respect to 11β-hydroxylase (CYP11B1, IC50 of 285 nM). The excellent inhibitory activity and selectivity of compound X21 are likely due to the presence of the hydroxymethyl group, which hydrogen bonds to the side chain of Asp309 in CYP19A1 but not in CYP11B2, where it is placed into a small lipophilic pocket.
To further characterize the potential effects of compound X21 on metabolic stability, in vitro assays against cytochromes P450 1A2 (CYP1A2) and 3A4 (CYP3A4) were also conducted. The latter enzymes were selected among those normally expressed in cells due to their major roles in the oxidation of xenobiotics (e.g., toxins and drugs). (63) Importantly, these assays revealed that compound X21 had marginal inhibitory activity of these enzymes, with the IC50 values being higher than 50 μM (Figure S2).
Finally, the benzylimidazole X21 was evaluated for its ability to cause antiproliferative and pro-apoptotic activity on two human BC cell lines (MCF-7, ER and PR positive, and MDA-MB-231, ER and PR negative) and one human normal dermal human fibroblast cell line (HNDF). The antiproliferative parameters, expressed in terms of IC50 values obtained after 24, 48, and 72 h of drug-exposure, are shown in Figure 5.

Figure 5

Figure 5. Antiproliferative in vitro effects of compound X21 and letrozole on human MCF-7 (Estrogen Receptor+), MDA-MB-231 (Estrogen Receptor−), and HNDF healthy cells at 24 h (A), 48 h (B), and 72 h (C). The data are presented as mean (±SEM) percentage values of vehicle-treated cell proliferation. Pro-apoptotic effects were observed in MCF-7 and MDA-MB-231 cells (D) using the cell death detection ELISA Plus kit. The internal negative control was provided by an ELISA kit. Columns and bars, mean values ± SD, respectively.

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Compound X21 showed a time- and concentration-dependent proliferation inhibition on both tested cancer cell lines (Figure 5). However, marked differences of potency were found between the two cell lines, the MCF-7 resulting in being the most sensitive cell line to compound X21 compared to MDA-MB-231 (Figure 5A–C). In particular, at 72 h, compound X21 inhibited the MCF-7 cell proliferation with an IC50 value of 0.26 ± 0.03 μM, whereas the antiproliferative activity on MDA-MB-231 was much lower (IC50 = 27.10 ± 5.15 μM; Figure 5C). Interestingly, compound X21 showed a similar activity to that of letrozole used as a reference (IC50 = 0.12 ± 0.03 μM; Figure 5C), as well as higher antiproliferative activity with respect to fadrozole (see Figure S3 in the Supporting Information). Remarkably, no significant antiproliferative effect on HNDF was found at the tested drug concentrations except for 50 μM (a 30% inhibition compared to vehicle; Figure 5C), thus confirming the lack of toxicity on normal cells. The apoptotic process was quantified using an ELISA test. Figure 5D shows a significant increase in the extent of DNA fragmentation at nanomolar concentrations of X21 after 24 h of exposure in MCF-7 cancer cells compared to vehicle-treated cells, whereas only higher concentrations (>40 μM) of compound X21 significantly increased the apoptotic signal in MDA-MB-231 cells (Figure 5D).
Searching for other molecular mechanisms underlying the pharmacological activity exhibited by X21, the ability of this compound to inhibit the phosphorylation of enzymes involved in the Akt/mTOR cell signaling pathway was investigated by luminex analysis of cell lysates. The activation of mTOR signaling in BC cells is associated with resistance to multiple drug therapies because the PI3K/Akt/mTOR axis represents an escape for the dependency from ER signaling. Indeed, the inhibition of mTOR has been shown to resensitize cells to the effects of tamoxifen. (64) Compound X21 was tested for its ability to inhibit protein phosphorylation in the MCF-7 cell line after 24 h exposure. As shown in Figure 6, the compound significantly inhibited mTOR phosphorylation (−30% vs control) at a concentration corresponding to its experimental IC50. A lower, but still significant, inhibition was also found in the phosphorylation of GSK3α and RP6S enzymes (Figure 6).

Figure 6

Figure 6. Luminex analysis of the Akt/mTOR cell signaling pathway in MCF-7 cells treated with compound X21 for 24 h at the experimental antiproliferative IC50 (700 nM). Results were reported as the percentage of the phosphorylated protein/total protein ratio vs 100% of vehicle-treated cells. C, vehicle-treated control; AKT, protein kinase B; GSK, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homologue; TSC2, tuberous sclerosis complex 2; RP6S, ribosomal protein S6; IGF1R, insulin-like growth factor 1 (IGF-1) receptor; IR, insulin receptor; IRS1, insulin receptor substrate 1; p70S6K, ribosomal protein S6 kinase beta-1. Columns and bars, mean values ± SD, respectively.

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Finally, in order to evaluate potential cardiovascular issues arising from the administration of compound X21, the compound was tested for its ability to interfere with the human cardiac potassium and sodium channels. To this aim, hERG and Nav1.5 manual patch clamp assays were conducted as described in the Methods section. Titration curves of compound X21 and the reference compounds E-4031 and tetrodoxin are reported in Figure S4. Satisfyingly, no significant inhibition of hERG and Nav1.5 was observed up to 10 and 30 μM concentrations, respectively, suggesting that compound X21 is potentially safe with respect to cardiotoxicity issues. As for the importance of balanced aldosterone levels in cardiac safety, the potent inhibition of aldosterone synthase CYP11B2 exerted by X21 is a major determinant of cardiac safety, which is inherent to the mechanism of action of this drug. (8,24)

Conclusions

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In this study, we describe the synthesis and computational analysis of a library of variously decorated benzylimidazole derivatives. The best candidates were biologically tested in an effort toward identifying potent and safe dual inhibitors of aromatase and aldosterone synthase. To this aim, 24 compounds with a benzylimidazole scaffold bearing different structural decorations were synthesized. The compounds were investigated by means of 2D- and 3D-similarity estimations made with LigAdvisor (25) and ROCS, (53) complemented by docking analyses into the investigated target enzymes, resulting in the selection of two candidates that were in vitro tested, namely, compounds X1 and X21. Compound X21 showed the desired, potent, and balanced dual inhibition of aromatase and aldosterone synthase and >10-fold selectivity with respect to 11β-hydroxylase, thus emerging as the best candidate. As such, compound X21 was further evaluated to assess its activity against additional selected cytochrome P450 enzymes responsible for metabolism of xenobiotics. The compound showed excellent antiproliferative and pro-apoptotic activity against the ER+ MCF-7 cell line. Of note, the same antiproliferative and apoptotic effects in ER-negative MDA-MB-231 cells were obtained at very high concentrations and were almost absent in normal human fibroblasts. Interestingly, compound X21 also showed characteristics to significantly inhibit the phosphorylation of mTOR in MCF-7 cells. Importantly, the compound showed negligible cardiotoxicity as assessed by hERG and Nav1.5 inhibition assays. Therefore, compound X21 stands out as a very interesting and promising candidate for further evaluation.

Experimental Section

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Chemistry

General Information

Unless specified, reagents were obtained from commercial sources and used without further purification. Solvents were obtained from Fischer Scientific. Melting points were recorded on an Optimelt automated melting point system and are uncorrected. The heating ramp gradient was set at 2.5 °C min–1. Flash chromatography was performed using Merck Silica gel high-purity grade (9385), pore size 60 Å, 230–400 mesh particle size. Thin-layer chromatography was performed using Merck TLC silica gel 60 with glass support. IR spectra were recorded neatly on a PerkinElmer Spectrum Two FT-IR spectrometer. The absorbency of the peaks was defined as weak (w, <40% of most intense peak), medium (m, 40–75% of the most intense peak), strong (s, >75% of the most intense peak), and broad (br). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III HD 400 spectrometer with operating frequencies of 400 MHz for 1H, 101 MHz for 13C. Proton chemical shift values are given in units δ relative to residual protic solvent. The multiplicity of the signal is indicated as br─broad, s─singlet, d─doublet, t─triplet, q─quartet, and m─multiplet, dd─doublet of doublets, dt─doublet of triplets, etc. Coupling constants (J) were measured to the nearest 0.1 Hz. Carbon chemical shift data are given in units δ relative to residual protic solvent. 2D NMR was used to aid the assignment of signal in 13C NMR. Liquid chromatography–mass spectrometry (LC-MS) was performed on a TQD mass spectrometer and an Acquity UPLC (Waters Ltd., UK).

Experimental Preparation for Compounds X4, X11–12, and X14–18

In a typical reaction, based upon 1 mmol of the free thiol; 2 equiv of the acceptor and 2 equiv of triethylamine were dissolved in a 1:1 mixture of DMSO:MeCN (2 mL each), the thiol was added, and the mixture was stirred at 90 °C for 2–4 h while monitoring by (EtOAc:hexane, 6:4). Upon completion, the reaction mixture was poured into water and the resulting solid filtered or extracted with EtOAc (2 × 25 mL), dried over MgSO4 and evaporated to dryness. Purification was performed by trituration, crystallization, or column chromatography as indicated.

(1-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-((2-nitro-5-(trifluoromethyl)phenyl)thio)-1H-imidazol-5-yl)methanol, Compound X17

Chemical formula: C19H14F3N3O5S.
Pale yellow solid isolated in 84% by crystallization from EtOAc:hexane 1:3; melting point 211.6–213.8 °C. LC-MS Rt 2.37 min m/z = 454.19 MeCN; HRMS calculated for C19H15N3O5S as 454.0679, found 454.0682 (Δ = 0.7 ppm); 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.6, 2.1 Hz, 1H), 7.30 (s, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 1.7 Hz, 1H), 6.53–6.43 (m, 2H), 5.84 (s, 2H), 5.52 (t, J = 5.1 Hz, 1H), 5.18 (s, 2H), 4.57 (br. s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 147.40 (C), 146.65 (C), 144.83 (C), 141.13 (C), 137.80 (C), 134.64 (C), 130.48 (CH), 130.35 (q, J = 3.3 Hz, CH), 130.24 (C), 129.64 (CH), 126.99 (q, J = 33.8 Hz, C), 123.30 (q, J = 271.7 Hz, C), 23.19 (q, J = 4.1 Hz, CH), 121.15 (CH), 108.24 (2 × CH), 101.40 (CH2), 53.72 (CH2), 48.16 (CH2); 19F NMR (376 MHz, DMSO-d6) δ −61.41; IR ν = 3133 br. w, 2909 br. w, 1622 w, 1567 w, 1528 m, 1492 m, 1446 m, 1422 m, 1326 s, 1301 s, 1247 s, 1152 s, 1121 s, 1031 s, 944 w, 925 m cm–1. *The signals for CH carbons correlating with the 1,3-benzodioxole ring signals at 6.55 and 6.48 appear coincident, as proven by HR-NMR and HSQC/HMBC 2D spectroscopy.
1H NMR (599 MHz, DMSO-d6) δ 8.35 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 7.27 (s, 1H), 6.61 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 7.9 Hz, 1H), 6.45 (dd, J = 7.9, 1.6 Hz, 1H), 5.82 (s, 2H), 5.49 (app t., J = 5.2 Hz, 1H), 5.16 (s, 2H), 4.55 (br. s, J = 3.4 Hz, 2H); 13C NMR (151 MHz, DMSO-d6) δ 147.39 (C), 146.64 (C), 144.82 (C), 141.10 (C), 137.78 (C), 134.63 (C), 130.46 (CH), 130.32 (q, J = 3.3 Hz, CH), 130.22 (C), 129.63 (CH), 126.99 (q, J = 34.0 Hz, C), 123.36 (q, J = 271.7 Hz, C), 123.15 (q, J = 4.1 Hz, CH), 121.32 (CH), 108.27 (CH), 108.22 (CH), 101.38 (CH2), 53.71 (CH2), 48.14 (CH2).

(2-((5-Chloro-2-nitrophenyl)thio)-1-(2-(thiophen-2-yl)ethyl)-1H-imidazol-5-yl)methanol, Compound X14

Chemical formula: C16H14ClN3O3S2.
Pale yellow solid isolated by trituration with 2:8 EtOAc:hexane in 73% yield; melting point 150.6–153.5 °C. LC-MS Rt 2.24 min m/z = 396.16 MeCN; HRMS calculated for C16H1535ClN3O3S2 as 396.0238, found 396.0244 (Δ = 1.5 ppm); 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.9 Hz, 1H), 7.51 (dd, J = 8.9, 2.2 Hz, 1H), 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.24 (s, 1H), 6.86 (dd, J = 5.1, 3.4 Hz, 1H), 6.68 (dd, J = 3.4, 1.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.41 (t, J = 5.3 Hz, 1H), 4.42 (d, J = 5.3 Hz, 2H), 4.32 (t, J = 7.0 Hz, 2H), 3.14 (t, J = 7.0 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 143.72 (C), 140.20 (C), 139.64 (C), 138.84 (C), 137.30 (C), 134.84 (C), 130.55 (CH), 128.49 (CH), 127.50 (CH), 127.22 (CH), 127.09 (CH), 126.50 (CH), 125.30 (CH), 53.62 (CH2), 46.66 (CH2), 30.73 (CH2); IR ν = 3164 br. w, 2905 br. w, 1622 w, 1584 w, 1554 w, 1505 m, 1445 m, 1419 m, 1330 s, 1301 m, 1229 m, 1149 w, 1137 m, 1088 w, 1029 s, 925 m cm–1.

(1-Benzyl-2-((2-nitro-4-(trifluoromethyl)phenyl)thio)-1H-imidazol-5-yl)methanol, Compound X12

Chemical formula: C18H14F3N3O3S.
Off-white solid isolated in 82% yield crystallized from MeOH:DCM 1:15; melting point 225.4–226.9 °C. LC-MS Rt 2.47 min m/z = 410.22; HRMS calculated for C18H15F3N3O3S as 410.0781, found 410.0770 (Δ = −2.7 ppm); 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.6, 2.1 Hz, 1H), 7.32 (s, 1H), 7.13–7.01 (m, 3H), 7.00–6.94 (m, 2H), 6.70 (d, J = 8.6 Hz, 1H), 5.46 (t, J = 5.2 Hz, 1H), 5.30 (s, 2H), 4.54 (d, J = 5.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 144.85 (C), 141.09 (C), 137.85 (C), 136.53 (CH), 134.83 (C), 130.66 (q, J = 3.4 Hz, CH), 130.55 (C), 129.60 (CH), 128.76 (2 × CH), 127.59 (CH), 127.30 (2 × CH), 127.05 (q, J = 33.8 Hz, C), 123.34 (q, J = 271.9 Hz, C), 123. 31 (q, J = 4.1 Hz, CH), 53.88 (CH2), 48.29 (CH2); 19F NMR (376 MHz, DMSO-d6) δ −61.41; IR ν = 3116 br. w, 2775 br. w, 1621 w, 1567 w, 1530 m, 1457 w, 1426 m, 1352 m, 1326 s, 1254 m, 1149 m, 1124 s, 1077 m, 1037 m, 905 m cm–1.

(1-Benzyl-2-((2-nitro-5-(trifluoromethyl)phenyl)thio)-1H-imidazol-5-yl)methanol, Compound X11

Chemical formula: C18H14F3N3O3S.
Pale yellow solid isolated in 77% yield by crystallization from 8:2 EtOAc:hexane, melting point 222.4–223.8 °C. LC-MS Rt 2.40 min m/z = 410.18; HRMS calculated for C18H15F3N3O3S as 410.0781, found 410.0789 (Δ = 2.0 ppm); 1H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J = 8.6, 1.0 Hz, 1H), 7.66 (dd, J = 8.6, 1.9 Hz, 1H), 7.34 (s, 1H), 7.03–6.94 (m, 5H), 6.74 (d, J = 1.9 Hz, 1H), 5.49 (br s, 1H), 5.34 (s, 2H), 4.56 (br s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 147.13 (C), 137.94 (C), 137.26 (C), 136.48 (C), 134.88 (C), 133.49 (q, J = 31.1 Hz, C), 130.49 (CH), 128.63 (CH), 127.64 (CH), 127.59 (CH), 127.29 (CH), 125.04 (q, J = 4.5 Hz, CH), 123.77 (q, J = 3.4 Hz, CH), 123.17 (q, J = 274.8 Hz, C), 53.81 (CH2), 48.37 (CH2); 19F NMR (376 MHz, DMSO-d6) δ −62.42; IR ν = 3133 br w, 2770 br w, 1641 w, 1536 m, 1465 w, 1430 m, 1418 w, 1350 s, 1330 s, 1253 m, 1155 s, 1128 s, 10827 s, 1035 m, 899 m cm–1.

(1-Benzyl-2-(methylthio)-1H-imidazol-5-yl)methanol, Compound X18

Chemical formula: C12H14N2OS.
White solid, isolated in 79% yield by column chromatography using EtOAc:hexane 7:3; melting point 104.7–106.8 °C (lit. m.p. 103–105 °C EtOAc). (65) LC-MS Rt 0.814 min m/z 235.18; HRMS calculated for C12H15N2OS as 235.0900, found 235.0895 (Δ = −2.1 ppm); 1H NMR (400 MHz, DMSO-d6) δ 7.38–7.31 (m, 2H), 7.30–7.23 (m, 1H), 7.13–7.04 (m, 2H), 6.95 (s, 1H), 5.23 (app. t, J = 5.0 Hz, 3H), 4.35 (d, J = 5.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 143.23 (C), 137.50 (C), 134.40 (C), 129.06 (2 × CH), 128.13 (CH), 127.84 (CH), 126.89 (2 × CH), 53.61 (CH2), 47.30 (CH2), 16.25 (CH3); IR ν = 3117 br w, 2839 br w, 2738 br w, 1604 w, 1501 m, 1445 s, 1415 s, 1372 m, 1308 s, 1279 m, 1183 w, 1141 m, 1082 w, 1016 s, 975 m, 914 w cm–1.

(1-Benzyl-2-((5-chloro-2-nitrophenyl)thio)-1H-imidazol-5-yl)methanol, Compound X4

Chemical formula: C17H14ClN3O3S.
Yellow solid isolated in 76% using trituration with EtOAc:Hexane 2:10, melting point 186–188.5 °C. LC-MS Rt 2.76 min m/z = 376.21 MeCN; HRMS calculated for C17H1535ClN3O3S as 376.0517, found 376.0519 (Δ = 0.5 ppm); 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.8, 2.3 Hz, 1H), 7.29 (s, 1H), 7.17–7.10 (m, 3H), 7.00–6.94 (m, 2H), 6.56 (d, J = 8.8 Hz, 1H), 5.44 (br s, 1H), 5.29 (s, 2H), 4.50 (s, 2H); 13C NMR (101 MHz, DMSO) δ 145.41 (C), 137.62 (C), 136.66 (C), 135.34 (C), 134.70 (C), 134.54 (CH), 131.08 (C), 130.40 (CH), 129.82 (CH), 128.84 (2 × CH), 127.60 (CH), 127.16 (2 × CH), 125.75 (CH), 53.90 (CH2), 48.22 (CH2); IR ν = 3127 br w, 1655 w, 1590 m, 1561 w, 1514 m, 1455 m, 1420 m, 1331 s, 1305 s, 1124 m, 1038 m, 1000 w, 860 m, 831 m cm–1.

(1-Benzyl-2-((3,5-dichloro-2,6-difluoropyridin-4-yl)thio)-1H-imidazol-5-yl)methanol, Compound X15

Chemical formula: C16H11Cl2F2N3OS.
Pale tan solid isolated in 34% yield as a mixture with X16 following separation using column chromatography with EtOAc:hexane 8:2; melting point 191.0 °C (decompose). LC-MS (MeCN) Rt 2.64 min m/z = 421.18; HRMS calculated for C16H1235Cl2F2N3OS as 421.0025, found 421.0021 (Δ = −1.0 ppm); 1H NMR (400 MHz, DMSO-d6) δ 7.33–7.17 (m, 3H), 7.11 (s, 1H), 7.03–6.93 (m, 2H), 5.43–5.36 (m, 3H), 4.44 (d, J = 4.8 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 156.46 (C), 154.06 (C), 147.57 (C), 144.84 (dd, J = 220.1, 14.8 Hz, C), 129.76 (CH), 129.43 (d, J = 5.9 Hz, C), 128.86 (2 × CH), 128.05 (CH), 126.28 (2 × CH), 118.88 (d, J = 34.6 Hz, C), 53.68 (CH2), 48.14 (CH2); 19F NMR (376 MHz, DMSO-d6) δ −70.02; IR ν = 3183 br. w, 2958 br. w, 1654 br. m, 1543 m, 1496 w, 1450 m, 1421 m, 1355 s, 1334 s, 1253 w, 1145 w, 1096 w, 1034 s, 1028 m, 833 s cm–1.

1-Benzyl-2-((3,5-dichloro-2,6-difluoropyridin-4-yl)thio)-1H-imidazole-5-carbaldehyde, Compound X16

Chemical formula: C16H9Cl2F2N3OS.
Off white solid generated by air oxidation of compound X15 in 56% yield following separation using column chromatography with EtOAc:hexane 8:2; melting point 107.8–110.9 °C. LC-MS Rt 2.87 min m/z = 400.15 and 402.13 MeCN; HRMS calculated for C16H10Cl2F2N3OS as 417.9790, found 417.9783 (Δ = −1.7 ppm); 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.06 (s, 1H), 7.45–7.21 (m, 3H), 7.18–7.05 (m, 2H), 5.69 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 180.50 (CH), 154.45 (dd, J = 246.2, 15.3 Hz, C), 147.35 (t, J = 1.5 Hz, C), 145.07 (C), 144.23 (C), 135.93 (C), 133.47 (C), 129.17 (2 × CH), 128.38 (CH), 126.91 (2 × CH), 117.78 (d, J = 40.2 Hz, C), 49.52 (CH2); 19F NMR (376 MHz, DMSO-d6) δ −70.77; IR ν = 3085 br w, 1667 s, 1577 s, 1528 w, 1495 w, 1445 m, 1397 m, 1393 s, 1336 m, 1273 w, 1246 w, 1099 w, 1029 w, 938 w, 881 s cm–1.

4-((5-(Hydroxymethyl)-1H-imidazol-1-yl)methyl)benzonitrile, Compound X21

Deamination was performed following the procedure described in refs (66) and (39).
Chemical formula: C12H11N3O.
White solid; melting point 167.3–168.5 °C. (Lit 168.0 °C); (1,2) LC-MS Rt 0.51 min m/z = 214.20 MeCN; HRMS calculated for C12H12N3O as 214.0980, found 214.0980 (Δ = 0.0 ppm); 1H NMR (400 MHz, DMSO-d6) δ 7.86–7.81 (app. d, J = 8.3 Hz, 2H), 7.73 (d, J = 1.1 Hz, 1H), 7.34–7.28 (app. d, J = 8.3 Hz, 2H), 6.87 (s, 1H), 5.36 (s, 2H), 4.31 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 143.91 (C), 139.17 (CH), 133.05 (2 × CH), 132.09 (C), 128.23 (2 × CH), 128.08 (CH), 119.14 (C), 110.75 (C), 53.14 (CH2), 47.58 (CH2); IR ν = 3128 br w, 2927 br w, 2846 br w, 2231 m, 1609 w, 1565 w, 1495 m, 1415 m, 1326 w, 1248 m, 1211 w, 1104 m, 1027 s, 966 w, 934 w cm–1.

4-((5-((4-(3-Chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile, Compound X22

The compound was prepared according to the procedure outlined in ref (39).
Orange solid; melting point 73.0 °C (decompose) (X22·H2O form lit. m.p. 90.0 °C). (39) LC-MS Rt 1.43 min m/z = 406.35 MeCN; HRMS calculated for C22H21ClN5O as 406.1429, found 406.1432 (Δ = 0.7 ppm); 13C NMR (101 MHz, DMSO-d6) δ 166.04 (C), 143.67 (C), 143.60 (C), 140.68 (CH), 133.34 (C), 132.91 (CH), 130.81 (CH), 128.87 (CH), 128.25 (CH), 126.71 (CH), 126.15 (CH), 124.53 (CH), 119.00 (C), 111.50 (C), 56.95 (CH2), 50.46 (CH2), 49.16 (CH2), 48.75 (CH2), 48.59 (CH2); IR ν = 3394 br w, 3068 br w, 2229 w, 1657 s, 1592 m, 1480 m, 1419 m, 1341 s, 1323 m, 1160 m, 1114 m, 1080 w, 1021 w cm–1.

Computational Methods

Computational Investigations Made with the LigAdvisor Web Server

The investigated compounds were each separately sketched into a dedicated “Structure search” input box available in the “Search in LigAdvisor” panel of the LigAdvisor web server (https://ligadvisor.unimore.it/, accessed on July 2nd, 2021). (26) The searches were carried out by selecting the “MACCS or ECFP4” type of similarity and setting minimum thresholds of 80 and 30% (i.e., Tanimoto Indexes equal to 0.8 and 0.3) for MACCS and ECFP4 fingerprints, respectively. Similarity records and related target annotations of DrugBank and PDB ligands were than analyzed in KNIME. (67)

CYP19A1, CYP11B1, and CYP11B2 Data Set Generation

ChEMBL Data Set
CYP19A1, CYP11B1, and CYP11B2 inhibitors were collected from the ChEMBL database (accessed on May 1st, 2020) and filtered to retain molecules that have reported activity annotations complying with the following criteria:

  • Target type equal to “Single Protein”;

  • Standard type expressed as Ki, Kd, IC50, EC50, potency;

  • Standard relation equal to “>” or “=”.

Moreover, filtered compounds were also desalted, and molecules with a molecular weight higher than 900 Da were removed. This phase of the ChEMBL data set preparation was performed by means of an in-house developed KNIME workflow. (67) Afterward, the most relevant ionization and tautomeric states potentially accessible at a physiological pH by the prefiltered known inhibitors were generated with the LigPrep utility. (68) Default settings were used in this phase of the preparation of CYP19A1, CYP11B1, and CYP11B2 inhibitors, except for the generation of every possible stereoisomer for compounds with undefined stereochemistry. Subsequently, up to 50 conformers were generated for each of the ligands with the oeomega module (OpenEye). (69) A cutoff of 0.5 Å on root-mean-square deviation (RMSD) and an energy window of 10 kcal/mol were used as parameters to accept conformers during the conformational sampling.
DrugBank Data Set
The open data set of DrugBank compounds was first downloaded (accessed on May 1, 2023) and associated with target activity annotations. Only compounds with annotations on CYP19A1, CYP11B1, and CYP11B2 were retained. Again, ligands with a molecular weight higher than 900 Da were removed and desalted, by means of an in-house developed KNIME workflow. Afterward, the compounds were prepared, and their multiconformers were generated for the 3D similarity estimations using the same modalities described for the ChEMBL data set (vide supra).
PDB Data Set
X-ray crystallographic complexes of CYP19A1, CYP11B1, and CYP11B2 were first retrieved from the Protein Data Bank (accessed on May 1st, 2020). (43) Then, their cocrystallized ligands were manually extracted in their bioactive conformation. Afterward, the compounds were filtered to retain only those accommodating in proximity to the HEME group and with a molecular weight ranging from 100 to 900 Da. Potential issues in the tautomerization state, atom typing, and in their stereochemistry were fixed, and hydrogen atoms were eventually added.

3D Ligand-Based Analyses

The investigated compounds were first sketched with the 2DSketcher utility implemented in Maestro of the Schrodinger suite and then prepared for the 3D similarity estimations as follows. Two databases containing up to 5 and 50 conformers of each synthesized ligand were generated with default settings of the oeomega module (OpenEye), (69) the first one being employed in the similarity assessments against the DrugBank and ChEMBL curated data sets, the second one being used in the ligand-based estimations against PDB cocrystallized compounds (vide supra). The similarity profile of each synthesized ligand was subsequently calculated with respect to compounds with activity annotations reported for CYP19A1, CYP11B1, and CYP11B2 into the DrugBank, ChEMBL and PDB databases, through a series of 3D similarity screenings made with ROCS (OpenEye). (53) Default settings were used in all of the performed 3D similarity estimations, except for the selection of the queries for the screenings. In particular, the native poses of the CYP19A1, CYP11B1, and CYP11B2 crystallographic ligands were used as queries in the similarity assessments of the synthesized compounds against the curated PDB data set. Conversely, a multiconformers vs multiconformer approach was applied to evaluate the similarities with respect to compounds in the curated DrugBank and ChEMBL data sets. The Tanimoto Combo coefficient was selected as a metric to establish ligand similarity, with a threshold of 1.5 according to literature data. (52) Postprocessing and statistics of the 3D similarity screenings were performed with KNIME. (67)

In Silico Tautomer Stability Assessment for Compound X1

The tautomeric preference of compound X1 was evaluated by using the Geometry Optimization and Single Point Energy protocols available in Jaguar (Schrödinger). (62) Default settings were used for the calculations, which were carried out with the DFT theory level, a B3LYP/3-61G** basis set, and an extended DFT grid and by selecting PBF-Water as solvent model.

Structure-Based Analyses

The structural complementarity of the synthesized compounds with the CYP19A1, CYP11B1, and CYP11B2 binding sites was also evaluated by means of molecular docking calculations performed with FRED (OpenEye). (58) To this aim, the 3EQM, (59) 4FDH,51 and 6M7X (49) crystal structures were selected as representative conformations of the CYP19A1, CYP11B2, and CYP11B1 enzymes, respectively. In particular, the 3EQM PDB complex was selected as a representative structure of CYP19A1 due to the unavailability of complexes of this target with nonsteroidal ligands, and because of its higher resolution (i.e. 2.9 Å). (59) 4FDH51 and 6M7X (49) PDB complexes were selected as representatives of the CYP11B2 and CYP11B1 enzymes, respectively, as they have been cocrystallized with (R)-fadrozole (PDB ID: 4FDH; PDB ligand ID: 0T3) and (S)-fadrozole (PDB ID: 6M7X; PDB ligand ID: JTD), which emerged in the similarity estimations; the selection of these structures is in line with good practices of structure-based multitarget drug design. (70,71) The selected structures were first prepared for docking by using default parameters via the Protein Preparation Wizard utility (Schrödinger). (72) Receptor grids were generated by means of the Make_receptor application (OpenEye). Default parameters were used for the generation of the 3EQM, 4FDH, and 6M7X receptor grids, which were centered on the coordinates of their cocrystallized ligands. The HEME group present in the structures was considered to be part of the receptor during the generation of the grids and in the following docking process. Once the grids were generated, redocking calculations were performed in order to assess the ability of the docking protocol to reproduce the native binding mode (RMSDs between the redocking and crystallographic poses below 2.0 Å) (Figure S1e–g). Finally, the validated docking models were used to predict the binding mode of the synthesized compounds into the CYP19A1, CYP11B2, and CYP11B1 selected crystal structures. Docking scores were analyzed and compared to those obtained for the native ligands. The predicted docking poses were visually inspected, and the best candidates were finally selected.

Biological Assays

In Vitro Assays on Recombinant CYP19A1, CYP1A2, and CYP3A4 Enzymes

The IC50 value of compound X21 against CYP19A1 was evaluated by means of an Aromatase (CYP19A1) Inhibitor Screening Kit from BioVision. The testes compound was first suspended at a concentration of 10 mM, and then tested in 10-dose IC50 mode with a 3-fold serial dilution, starting from a concentration of 10 μM. Letrozole was used as a control in this assay (starting from a 1 μM concentration). The in vitro tests on Aromatase were performed by using the Kit Cat# K984-100 assay kit; the Regeneration System, 100× and NADP+: (100×), 10 mM were used as reaction buffer. In particular, the enzyme was first prepared with the Regeneration System and substrate with NADP+ in freshly prepared reaction buffer. Then, the resulting solution was delivered into the reaction well. Afterward, compound X21 and the control compound were delivered into the enzyme solution by Acoustic technology (Echo550; nanoliter range) and incubated for 20 min at room temperature. Subsequently, a solution of the CYP19A1 substrate was delivered into the reaction well to initiate the reaction at 37 °C. The enzyme activities were monitored as a time-course measurement of the increase in fluorescence signal from fluorescence substrate for 60 min, at 37 °C in EnVision (Ex 485/Em 535 nm).
The assays on CYP1A2 and CYP3A4 were based on the fluorescence read out using Vivid fluorescence substrates against CYP BACULOSOMES from ThermoFisher Scientific. The test compound was first suspended at a concentration of 10 mM and tested in 10-dose IC50 mode with a 3-fold serial dilution, starting from a concentration of 10 μM. The in vitro tests on CYP1A2 and CYP3A4 were performed by using the Kit Cat# P2863 and P2858 assay kits, respectively; 100 mM potassium phosphate buffer (pH 8.0), and 1% DMSO, Vivid Regeneration System, 100× (333 mM glucose-6-phosphate and 30 U/mL glucose-6-phosphate dehydrogenase in 100 mM potassium phosphate, pH 8.0) and NADP+: (100×), 10 mM were used as reaction buffer. IC50 values of compound X21 against CYP3A4 and CYP1A2 were determined with the same modalities described above, except for: (i) the use of control compounds Ketoconazole (CYP3A4), and Furafylline (CYP1A2), which were tested in a 10-dose IC50 mode with 3-fold serial dilution starting from 1 and 20 μM, respectively; (ii) the use of substrates specific for CYP1A2 (10 μM Vivid EOMCC Substrate) and CYP3A4 (10 μM Vivid BOMCC Substrate), and; (iii) enzyme activity monitoring, which was determined through a time-course measurement of the increase in fluorescence signal from fluorescence substrate for 100 min at room temperature in EnVision (Ex 405/Em 460 nm).

Pharmacological Assays

Materials, Drugs, and Cells Lines

Recombinant human epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were obtained from PeproTechEC LTD (London, UK). Cell culture media, MCDB-131, RPMI-1640, fetal bovine serum (FBS), l-glutamine, and antibiotics were from Gibco (ThermoFisher Scientific, Waltham, MA, USA). Type A gelatin from porcine skin, supplements, and all other chemicals not listed in this section were from Sigma Chemical Co. (St. Louis, MO, USA). Plastics for cell culture were supplied by Sarstedt (Nümbrecht, Germany).
The human breast cancer cell lines MCF-7 and MDA-MB-231 were obtained from the American Type Culture Collection (ATCC; Manassas, USA) and maintained in 20% FBS RPMI-1640 medium supplemented with antibiotics and 2 mM l-glutamine, whereas human normal dermal human fibroblast cells (HNDF; ATCC) were maintained in MCDB-131 culture medium supplemented with antibiotics, 20% heat-inactivated FBS, l-glutamine (2 mM), heparin (10 IU/mL), rhEGF (10 ng/mL), and rhbFGF (5 ng/mL). Cell lines were routinely grown in tissue culture flasks, covered with type A gelatin only for HNDF, and kept in a humidified atmosphere of 5% CO2 at 37 °C.
In vitro pharmacological studies were performed using drugs diluted from a 10 mM stock solution (in 100% dimethyl sulfoxide). DMSO concentration in the control’s media was the one utilized to dilute the highest concentration of compound X21 in the medium of treated samples for the same experiment.

Cell Proliferation and Apoptosis Assay

MCF-7 and MDA-MB-231 cells were plated in 24-well plates and allowed to attach overnight. Cells were treated with compound X21 (0.001–50 μM) or with its vehicle for 24, 48, and 72 h. HNDF cells were exposed to compound X21 for 72 h, whereas MCF-7 cells were also treated for 72 h with letrozole (0.001–50 μM), as a positive control. At the end of the treatment, viable cells (evaluated by trypan blue dye exclusion) were counted with a hemocytometer. The concentration of drug that reduced cell proliferation by 50% (IC50) vs controls was calculated by nonlinear regression fit of the mean values of data obtained in triplicate experiments (at least nine wells for each concentration).
To quantify apoptosis induced by compound X21, 30 × 104 MCF-7 or MDA-MB-231 cells were plated in 100 mm sterile dishes and treated for 24 h with different concentrations of X21 (0.35, 0.7, and 1 μM for MCF-7; 10, 40, and 50 μM for MDA-MB-231, and with vehicle alone. At the end of the incubation, cells were collected, and the samples were analyzed with the cell death detection enzyme-linked immunosorbent assay (ELISA) Plus kit (Roche, Switzerland). All experiments were repeated three times with at least three replicates per sample.

Luminex Analysis

MCF-7 cells (5 × 104) were plated and treated with compound X21 (700 nM, the experimental antiproliferative IC50) and vehicle alone for 24 h (three replicates per sample). At the end of the experiment, the cells were lysed at 4 °C with Milliplex lysis buffer supplemented with protease inhibitors, and then the samples were filtered with Ultrafree-MC centrifugal filter devices with microporous membranes from MerckMillipore (Merck KGaA, Darmstadt, Germany). Twenty-five microliters of filtered lysate was diluted in assay buffer (1:2 v:v, respectively), and then a 25 μL sample of the solution was evaluated by Luminex using the MILLIPLEX Akt/mTOR Phosphoprotein 11-plex Magnetic Bead kit (catalogue #48-611MAG kit) purchased from MerckMillipore. The samples were loaded into a 96-well plate supplied by the kit. In each well, an equal volume of a premix of 11 luminex beads was added, followed by incubation overnight at 4 °C. The beads were subsequently washed and incubated with 25 μL of secondary biotinylated detection antibody for 1 h at room temperature, according to the manufacturer’s protocol. The samples were analyzed by a FlexMap3D instrument (MerckMillipore) with xPONENT software (MerckMillipore) following the manufacturer’s protocols and settings. Results were reported as the percentage of the phosphorylated protein/total protein ratio vs 100% of vehicle-treated cells.

Statistical Data Analysis

The analysis by ANOVA, followed by the Student–Newman–Keuls test, was used to assess the statistical differences of pharmacological data in vitro. P-values lower than 0.05 were considered significant. Statistical analyses were performed using the GraphPad Prism software package, version 5.0 (GraphPad Software Inc., San Diego, CA, USA).

Cardiac Safety Assessment

Compound activity against the voltage-gated potassium channel hERG and sodium channel Nav1.5 was assessed to evaluate the potential cardiac liabilities. The assays on hERG were performed by means of the Manual hERG Patch Clamp Assay in CHO-hERG cells. To this aim, electrodes (2.5–4 MW) were filled with intracellular solution (in mM): KCl (120), HEPES (10), CaCl2 (10), MgCl2 (1.7), EGTA (10), K2ATP (4), pH 7.2, approximately 290 mOsM. Cells were continuously perfused in extracellular solution containing (in mM): NaCl (145), KCl (4) CaCl2 (2), MgCl2 (1), HEPES (10), pH 7.4, approximately 305 mOsM. The voltage protocol in this assay started with a holding potential equal to −80 mV and hyperpolarization equal to +40 mV for 500 ms, followed by a ramp of 100 ms with −80 mV potential, repeated every 5 s. hERG current is defined as peak current elicited by Ramp in pA. Compound X21 was added via continuous perfusion until the hERG current reached a plateau. Six concentrations of compound X21 were added from lowest concentration to highest (10 μM), with a 3-factor dilution. A 10-μM solution of E-4031 was added after the X21 curve was completed to establish full blockade of the hERG current. All recordings were performed at room temperature.
The assays on sodium Nav1.5 ion channel were performed by means of Manual Patch Clamp Assay, in HEK-NaV1.5 stable cells. To this aim, GC150TF-10 electrodes (1.5 Outer diameter × 1.17 inner diameter × 100 length [mm], 3–5 MOhm) were filled with intracellular solution (in mM): KCl (120), HEPES (10), CaCl2 (5), MgCl2 (1.7), K2ATP (4), EGTA (10), pH 7.2, approximately 290 mOsM. Cells were continuously perfused in extracellular solution containing (in mM): NaCl (145), KCl (4), CaCl2 (2), MgCl2 (1), HEPES (10), d-glucose (10), pH 7.4, approximately 305 mOsM.
The voltage protocol was conducted first with a holding potential equal to −80 mV and hyperpolarization equal to −120 mV for 500 ms, followed by a step of 4 ms with a −15 mV potential, repeated every 5 s. Nav1.5 current was defined as negative peak current elicited by Step to −15 mV in pA. Compound X21 was tested in 6-point IC50 mode, with a 3-fold dilution, starting at a maximum concentration of 30 μM. DMSO was added to all compound solutions up to a final concentration of 0.3%. The control compound tetrodotoxin was tested in 7-point IC50 mode, with a 3-fold dilution starting at a maximum concentration of 10 μM. All recordings were performed at room temperature.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.3c00183.

  • Results of the similarity estimations performed with the LigAdvisor Web server; results of the similarity estimations performed with respect to compounds with activity annotation on CYP19A1, CYP11B2, and CYP11B1, reported in the DrugBank, PDB, and ChEMBL databases; docking scores of the investigated compounds into the PDB crystal structures 3EQM (CYP19A1), 6M7X (CYP11B1), and 4FDH (CYP11B2); binding mode predicted for (S)- and (R)-fadrozole into the CYP19A1 binding site (PDB ID: 3EQM); titration curves of compound X21 against CYP19A1, CYP1A2, and CYP3A4, with their respective controls; antiproliferative in vitro activity of fadrozole on human MCF-7 (Estrogen Receptor+) at 24, 48, and 72 h; and titration curves of compound X21 and the reference compounds E-4031 and tetrodoxin, against hERG and Nav1.5 (manual patch clamp assays), respectively (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Annachiara Tinivella - Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
    • Marta Banchi - Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
    • Guido Gambacorta - Department of Chemistry, University of Durham, Lower Mount Joy, South Rd, Durham DH1 3LE, U.K.
    • Federica Borghi - Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi, Modena 41125, Italy
    • Paola Orlandi - Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
    • Ian R. Baxendale - Department of Chemistry, University of Durham, Lower Mount Joy, South Rd, Durham DH1 3LE, U.K.;  Orcidhttps://orcid.org/0000-0003-1297-1552
    • Antonello Di Paolo - Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
    • Guido Bocci - Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa 56126, Italy
  • Author Contributions

    A.T. and L.P. performed the computational analyses. M.B. and P.O. performed the pharmacological assays. G.G. performed the synthesis of the compounds. F.B. and G.B. wrote the initial draft. I.R.B. supervised the synthesis work. A.D.P and G.B. supervised the pharmacological assays. G.R. conceptualized the work and supervised the modeling work. The manuscript was drafted and revised by all the authors. All authors approved the final version of the manuscript.

  • Funding

    G.R. was supported by FAR─Fondo di Ateneo per la Ricerca 2019 [166835 of 2019/30/07]; A.T. was supported by a PhD fellowship from the Regione Emilia-Romagna on Data driven technologies for drug repurposing; L.P. received a grant from the Italian funding program Fondo Sociale Europeo REACT-EU─PON “Ricerca e Innovazione” 2014–2020─Azione IV.4 “Dottorati e contratti di ricerca su tematiche dell’innovazione”; M.B. was supported by PNRR─Tuscany Health Ecosystem (THE)─CUP 153C22000780001─Spoke n. 7─Innovating Translational Medicine.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank OpenEye Scientific Software, Inc. for a free academic license. We wish to thank Dr. Arianna Bandini for technical assistance.

Abbreviations

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ACE

angiotensin-converting enzyme

AI

aromatase inhibitor

AKT

protein kinase B

Ang II

angiotensin II

AT1R

angiotensin type 1 receptor

ATCC

American Type Culture Collection

BC

breast cancer

bFGF

basic fibroblast growth factor

C

vehicle-treated control

CVD

cardiovascular disease

CYP11B1

cytochrome P450 family 11 subfamily B member 1

CYP11B2

aldosterone synthase

CYP19A1

aromatase

CYP1A2

cytochromes P450 1A2

CYP3A4

cytochromes P450 3A4

EGF

epidermal growth factor

ERBB2/HER2+

human epidermal growth factor receptor-2 positive

ER

estrogen receptor

FBS

foetal bovine serum

GSK

glycogen synthase kinase 3

HNDF

human normal dermal human fibroblast cell line

IGF1R

insulin-like growth factor 1 (IGF-1) receptor

IR

insulin receptor

IRS1

insulin receptor substrate 1

mTOR

mammalian target of rapamycin

MW

molecular weight

p70S6K

ribosomal protein S6 kinase beta-1

PDB

protein data bank

PR

progesterone receptor

PTEN

phosphatase and tensin homologue

RAAS

renin–angiotensin–aldosterone system

RMSD

root-mean-square deviation

RP6S

ribosomal protein S6

SERD

selective estrogen receptors degrader

SERM

selective estrogen receptors modulator

TSC2

tuberous sclerosis complex 2

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    Circulation Journal (2010), 74 (4), 634-643CODEN: CJIOBY; ISSN:1346-9843. (Japanese Circulation Society)
    Background: Female sex hormones may have protective effects against arrhythmias, including reperfusion arrhythmias (RAs), but the mechanisms are still not completely known. Methods and Results: Serial changes in rat hearts (rhythm, apoptosis and the its influencing factors; cardiac vinculin mRNA expression and connexin43 (Cx43) dephosphorylation) were examd. during periods of ischemia-reperfusion with and without estrogen treatment. After reperfusion, although the incidence of arrhythmias became higher in both the vehicle-group and estrogen-group, compared with the ischemia period, estrogen prevented reperfusion-induced upregulation of the incidence of arrhythmias, esp. ventricular premature beats (VPB) and ventricular tachycardia (VT). The duration of VT and fibrillation, and the no. of VPB and VT, were all significantly decreased in the estrogen-group. The expression of cardiac vinculin mRNA decreased significantly in the vehicle-group but not in the estrogen-group. Cx43 dephosphorylation and myocyte apoptosis increased in both groups, but the values for the estrogen-group were all markedly lower than those for the vehicle-group. A selective estrogen receptor (ER) β agonist prevented reperfusion-induced upregulation of the incidence of both VPB and VT significantly; a selective ERα agonist had no significant influence. Conclusions: Estrogen can protect the heart against RAs, at least in part, mediated through gap junctions. Upregulation of ERβ but not ERα mediated most of the estrogen-induced cardioprotection against RA.
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  12. 12
    Beer, S.; Reincke, M.; Kral, M.; Callies, F.; Strömer, H.; Dienesch, C.; Steinhauer, S.; Ertl, G.; Allolio, B.; Neubauer, S. High-Dose 17β–Estradiol Treatment Prevents Development of Heart Failure Post–Myocardial Infarction in the Rat. Basic Res. Cardiol. 2007, 102 (1), 9– 18,  DOI: 10.1007/s00395-006-0608-1
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    12
    High-dose 17β-estradiol treatment prevents development of heart failure post-myocardial infarction in the rat
    Beer, Stephanie; Reincke, Martin; Kral, Maike; Callies, Frank; Stroemer, Hinrik; Dienesch, Charlotte; Steinhauer, Sonja; Ertl, Georg; Allolio, Bruno; Neubauer, Stefan
    Basic Research in Cardiology (2007), 102 (1), 9-18CODEN: BRCAB7; ISSN:0300-8428. (Steinkopff Verlag)
    Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or β-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examd. whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. Female rats were treated with 17β-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to exptl. myocardial infarction. Eight weeks after infarction, in vivo echocardiog. and hemodynamic measurements as well as isolated heart perfusion were performed. In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diams. (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-vol. curves occurring in untreated infarcted hearts was completely prevented by estrogen. High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment. However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.
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  13. 13
    Gardner, J. D.; Murray, D. B.; Voloshenyuk, T. G.; Brower, G. L.; Bradley, J. M.; Janicki, J. S. Estrogen Attenuates Chronic Volume Overload Induced Structural and Functional Remodeling in Male Rat Hearts. Am. J. Physiol.-Heart Circ. Physiol. 2010, 298 (2), H497– H504,  DOI: 10.1152/ajpheart.00336.2009
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  14. 14
    Donaldson, C.; Eder, S.; Baker, C.; Aronovitz, M. J.; Weiss, A. D.; Hall-Porter, M.; Wang, F.; Ackerman, A.; Karas, R. H.; Molkentin, J. D.; Patten, R. D. Estrogen Attenuates Left Ventricular and Cardiomyocyte Hypertrophy by an Estrogen Receptor–Dependent Pathway That Increases Calcineurin Degradation. Circ. Res. 2009, 104 (2), 265– 275,  DOI: 10.1161/CIRCRESAHA.108.190397
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    14
    Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway That Increases Calcineurin Degradation
    Donaldson, Cameron; Eder, Sarah; Baker, Corey; Aronovitz, Mark J.; Weiss, Alexandra Dabreo; Hall-Porter, Monica; Wang, Feng; Ackerman, Adam; Karas, Richard H.; Molkentin, Jeffery D.; Patten, Richard D.
    Circulation Research (2009), 104 (2), 265-275CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)
    Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a crit. role in the development of pathol. hypertrophy. Previous exptl. studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17β-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 wk, mice underwent physiol. evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were assocd. with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degrdn. that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degrdn., unveiling a novel mechanism by which E2 and ERs regulate pathol. LV and cardiomyocyte growth.
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  15. 15
    Arias-Loza, P.-A.; Muehlfelder, M.; Elmore, S. A.; Maronpot, R.; Hu, K.; Blode, H.; Hegele-Hartung, C.; Fritzemeier, K. H.; Ertl, G.; Pelzer, T. Differential Effects of 17β-Estradiol and of Synthetic Progestins on Aldosterone-Salt–Induced Kidney Disease. Toxicol. Pathol. 2009, 37 (7), 969– 982,  DOI: 10.1177/0192623309350475
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    15
    Differential effects of 17β-estradiol and of synthetic progestins on aldosterone-salt-induced kidney disease
    Arias-Loza, Paula-Anahi; Muehlfelder, Melanie; Elmore, Susan A.; Maronpot, Robert; Hu, Kai; Blode, Hartmut; Hegele-Hartung, Christa; Fritzemeier, Karl Heinrich; Ertl, Georg; Pelzer, Theo
    Toxicologic Pathology (2009), 37 (7), 969-982CODEN: TOPADD; ISSN:0192-6233. (Sage Publications)
    Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown. Identify the function of estrogens and of different synthetic progestins on aldosterone salt-mediated renal disease. The role of 17β-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment. Aldo-salt treatment of intact, ovariectomized, and estradiol-treated female rats resulted in remnant kidney hypertrophy without structural damage. Co-treatment with MPA, but not with drospirenone, increased kidney hypertrophy, fluid turnover, sodium retention, and potassium excretion. Medroxyprogesterone acetate also caused glomerular, vascular, tubular, and interstitial lesions that were accompanied by increased blood pressure and enhanced NADPH oxidase (p67phox) and sodium channel (α-ENaC) expression. Drospirenone, a progestin with anti-mineralocorticoid function, and spironolactone prevented kidney hypertrophy, hypertension, and sodium retention. Drospirenone and spironolactone also increased renal angiotensin II type 2 receptor expression and relieved aldosterone-induced suppression of serum angiotensin II levels. The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake.
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  16. 16
    Kwan, M. L.; Yao, S.; Laurent, C. A.; Roh, J. M.; Quesenberry, C. P.; Kushi, L. H.; Lo, J. C. Changes in Bone Mineral Density in Women with Breast Cancer Receiving Aromatase Inhibitor Therapy. Breast Cancer Res. Treat. 2018, 168 (2), 523– 530,  DOI: 10.1007/s10549-017-4626-5
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    16
    Changes in bone mineral density in women with breast cancer receiving aromatase inhibitor therapy
    Kwan, Marilyn L.; Yao, Song; Laurent, Cecile A.; Roh, Janise M.; Quesenberry, Charles P., Jr.; Kushi, Lawrence H.; Lo, Joan C.
    Breast Cancer Research and Treatment (2018), 168 (2), 523-530CODEN: BCTRD6; ISSN:0167-6806. (Springer)
    Purpose: We assessed bone mineral d. (BMD) change with aromatase inhibitor (AI) treatment in a contemporary cohort of women with breast cancer treated in Kaiser Permanente Northern California. Methods: Percent and estd. annual percent changes in BMD at the total hip and lumbar spine were examd. in 676 women receiving AI therapy who had two serial BMD reports available (at least 1 yr apart) before and after AI initiation (N = 317) or during continued AI therapy (N = 359). BMD changes were examd. at the total hip and lumbar spine and compared by age and clin. subgroups. Results: Women experienced BMD declines after AI initiation or continued therapy, with median annual percent change - 1.2% (interquartile range, IQR - 2.4 to - 0.1%) at the hip and - 1.0% (IQR - 2.3 to 0.1%) at the spine after AI initiation, and - 1.1% (IQR - 2.4 to 0.1%) at the hip and - 0.9% (IQR - 2.4 to 0.5%) at the spine during continued therapy. Higher levels of bone loss were obsd. among younger (< 55 years) compared with older (≥ 75 years) women at the hip (- 1.6% vs. - 0.8%) and at the spine (- 1.5% vs. - 0.5%) after AI initiation, and at the hip (- 1.4% vs. - 1.2%) and at the spine (- 2.4% vs. - 0.001%) during continued therapy. Conclusions: Small but consistent declines in total hip and lumbar spine BMD were present in breast cancer patients following AI therapy initiation or continued AI therapy. Although the overall rates of osteoporosis were low, greater estd. levels of annual bone loss were evident among women < 55 years.
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  17. 17
    Tian, W.; Wu, M.; Deng, Y. Comparison of Changes in the Lipid Profiles of Eastern Chinese Postmenopausal Women With Early-Stage Breast Cancer Treated With Different Aromatase Inhibitors: A Retrospective Study. Clin. Pharmacol. Drug Dev. 2018, 7 (8), 837– 843,  DOI: 10.1002/cpdd.420
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    17
    Comparison of Changes in the Lipid Profiles of Eastern Chinese Postmenopausal Women With Early-Stage Breast Cancer Treated With Different Aromatase Inhibitors: A Retrospective Study
    Tian, Wei; Wu, Miaowei; Deng, Yongchuan
    Clinical Pharmacology in Drug Development (2018), 7 (8), 837-843CODEN: CPDDAH; ISSN:2160-7648. (John Wiley & Sons, Inc.)
    Cardiovascular morbidity is closely assocd. with serum lipid level. We aimed to investigate the effects of different aromatase inhibitors, including letrozole, anastrozole, and exemestane, on the lipid profile of eastern Chinese breast cancer patients. We evaluated a retrospective cohort of eastern Chinese postmenopausal women with early-stage breast cancer who received aromatase inhibitors. A total of 116 postmenopausal women with early-stage breast cancer without prior cardiovascular disease were included. Lipid changes at 3, 6, 12, and 24 mo were compared across the endocrine therapy categories. Our data demonstrated that exemestane treatment significantly decreased triglyceride level compared with letrozole after 24 mo. However, the aromatase inhibitors had almost equiv. impacts on high-d. liportein cholesterol, low-d. lipoprotein cholesterol, and triglyceride after long-term aromatase inhibitor treatment. As a small-size retrospective study, our data do not support a judgment about whether one AI or another carries more or less risk in terms of lipid disorders in eastern Chinese breast cancer patients. The exact effects need further randomized, controlled trials to investigate.
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  18. 18
    Castelli, W. P. Cardiovascular Disease in Women. Am. J. Obstet. Gynecol. 1988, 158 (6), 1553– 1560,  DOI: 10.1016/0002-9378(88)90189-5
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    Cardiovascular disease in women
    Castelli W P
    American journal of obstetrics and gynecology (1988), 158 (6 Pt 2), 1553-60, 1566-7 ISSN:0002-9378.
    Cardiovascular disease is the leading cause of death in American women. Atherosclerotic diseases, primarily myocardial infarction and stroke, are important causes of morbidity and mortality among women. Contrary to popular belief, the actual number of myocardial infarctions in men and women is similar, although women develop cardiovascular disease an average of 10 years later than do men. Total serum cholesterol level is a major indicator of risk of coronary heart disease; for every 1% increase in the total serum cholesterol level, a 2% increase in incidence of coronary heart disease is found. A high level of low-density lipoproteins is an independent risk factor for coronary heart disease in both mean and women, but high triglyceride level is an independent risk factor only in women. Conversely, the higher the level of high-density lipoprotein, the lower the risk of coronary heart disease. To reduce the risk of coronary heart disease, target levels of total serum cholesterol must be lowered from 300 to 200 mg/dl. If the total cholesterol/high-density lipoprotein ratio is greater than or equal to 4.5 of if the low-density lipoprotein concentration is greater than 150 mg/dl, the patient is at high risk for coronary heart disease. Clinical trials that use diet or drugs to lower serum cholesterol levels have consistently shown a 2% reduction in the incidence of coronary heart disease for every 1% reduction in total serum cholesterol level.
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  19. 19
    Fischer, M. Renin Angiotensin System and Gender Differences in the Cardiovascular System. Cardiovasc. Res. 2002, 53 (3), 672– 677,  DOI: 10.1016/S0008-6363(01)00479-5
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    19
    Renin angiotensin system and gender differences in the cardiovascular system
    Fischer, Marcus; Baessler, Andrea; Schunkert, Heribert
    Cardiovascular Research (2002), 53 (3), 672-677CODEN: CVREAU; ISSN:0008-6363. (Elsevier Science B.V.)
    A review. To explain gender-related differences of the cardiovascular system, the renin-angiotensin system experienced intensive exploration. Indeed, the development of hypertension as well as the progression of coronary artery disease and heart failure have 2 factors in common: (1) display distinct gender specific characteristics and (2) are enhanced by the renin-angiotensin system. It is therefore interesting to note that data from exptl. animals, epidemiol. surveys, and clin. investigations suggest that the components of the circulating as well as tissue-based renin-angiotensin system are markedly affected by gender. However, the issue is complicated by counter-regulatory effects of estrogen on the system with the substrate, on one hand, and the processing enzymes as well as the chief receptor, on the other hand. In fact, angiotensinogen is up-regulated particularly by oral administration of estrogen, whereas renin, angiotensin-converting enzyme (ACE), and AT-1 receptor are down-regulated by the hormone. While under well-defined exptl. conditions the net effect of estrogen appears to result in suppression of the renin-angiotensin system, the clin. situation may be more complex. The judgment is further complicated by the difficulty in precisely measuring the activity of the system at the tissue level. Moreover, clin. relevant read-outs for the activity of the renin-angiotensin system may be regulated multifactorially or only indirectly affected by the system. Nevertheless, the undisputable, profound biochem. changes in the renin-angiotensin system related to the estrogen status allow speculation that such interaction explains some of the differences in the cardiovascular system of men and women.
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  20. 20
    Roesch, D. M.; Tian, Y.; Zheng, W.; Shi, M.; Verbalis, J. G.; Sandberg, K. Estradiol Attenuates Angiotensin-Induced Aldosterone Secretion in Ovariectomized Rats. Endocrinology 2000, 141 (12), 4629– 4636,  DOI: 10.1210/endo.141.12.7822
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    20
    Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats
    Roesch, Darren M.; Tian, Ying; Zheng, Wei; Shi, Min; Verbalis, Joseph G.; Sandberg, Kathryn
    Endocrinology (2000), 141 (12), 4629-4636CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)
    Estrogen replacement therapy significantly reduces the risk of cardiovascular disease in postmenopausal women. Previous studies indicate that estradiol (E2) decreases angiotensin II (AT) receptor d. in the adrenal and pituitary in NaCl-loaded rats. We used an in vivo model that eliminates the potentially confounding influence of ACTH to det. whether the E2-induced decrease in adrenal AT receptor expression affects aldosterone responses to angiotensin II (Ang II). Female rats were ovariectomized, treated with oil (OVX) or E2(OVX+E2; 10 μg, s.c.) for 14 days, and fed a NaCl-deficient diet for the last 7 days to maximize adrenal AT receptor expression and responsiveness. On days 12-14 rats were treated with dexamethasone (DEX; 25 μg, i.p., every 12 h) to suppress plasma ACTH. On day 14 aldosterone secretion was measured after a 30-min infusion of Ang II (330 ng/min). Ang II infusion increased the peak plasma aldosterone levels to a lesser degree in the OVX+E2 than in the OVX rats (OVX, 1870 pg/mL; OVX+E2, 1010 pg/mL). Ang II-induced ACTH and aldosterone secretion was also studied in rats that were not treated with DEX. In the absence of DEX, the peak plasma aldosterone response was also significantly decreased (OVX, 5360 pg/mL; OVX+E2, 2960 pg/mL). However, E2 also reduced the plasma ACTH response to Ang II (OVX, 220 pg/mL; OVX+E2, 160 pg/mL), suggesting that reduced pituitary ACTH responsiveness to Ang II contributes to the effect of E2 on Ang II-induced aldosterone secretion. Adrenal AT1 binding studies confirmed that E2 significantly reduces adrenal AT1 receptor expression in both the presence and absence of DEX in NaCl-deprived rats. These results indicate that E2-induced decreases in pituitary and adrenal AT1 receptor expression are assocd. with attenuated pituitary ACTH and adrenal aldosterone responses to Ang II and suggest that estrogen replacement therapy may modulate Ang II-stimulated aldosterone secretion as part of its well known cardioprotective actions.
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  21. 21
    Chappell, M. C.; Gallagher, P. E.; Averill, D. B.; Ferrario, C. M.; Brosnihan, K. B. Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat. Hypertension 2003, 42 (4), 781– 786,  DOI: 10.1161/01.HYP.0000085210.66399.A3
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    21
    Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2.Lewis rat
    Chappell, Mark C.; Gallagher, Patricia E.; Averill, David B.; Ferrario, Carlos M.; Brosnihan, K. Bridget
    Hypertension (2003), 42 (4, Pt. 2), 781-786CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
    The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 wk resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 wk, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195±3.7 mm Hg vs. 141±4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concn., as well as urinary excretion of Ang II, 8-isoprostane F2α, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 wk (125±2.9 mm Hg, n=7, P<0.01 vs. OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113±5.4 mm Hg (n=6, P<0.01 vs. OVX and sham). The attenuation of the hypertension was still evident 7 wk after complete withdrawal of treatment (124±4.1 mm Hg at week 23). In summary, the OVX mRen.2.Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2.Lewis strain, possibly by limiting activation of the renin-angiotensin system.
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  22. 22
    Harrison-Bernard, L. M.; Schulman, I. H.; Raij, L. Postovariectomy Hypertension Is Linked to Increased Renal AT1 Receptor and Salt Sensitivity. Hypertension 2003, 42 (6), 1157– 1163,  DOI: 10.1161/01.HYP.0000102180.13341.50
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    22
    Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity
    Harrison-Bernard, Lisa M.; Schulman, Ivonne Hernandez; Raij, Leopoldo
    Hypertension (2003), 42 (6), 1157-1163CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
    The functional balance between angiotensin II (Ang II) and nitric oxide (NO) plays a key role in modulating salt sensitivity. Estrogen has been shown to downregulate angiotensin type 1 (AT1) receptor expression and to increase the bioavailability of endothelium-derived NO, which decreases AT1 receptor expression. The present study tests the hypothesis that in the presence of genetic salt sensitivity, deficiency of endogenous estrogens after ovariectomy (OVX) fosters an upregulation of Ang II. Female Dahl salt-resistant (DR), Dahl salt-sensitive (DS), Wistar-Kyoto (WKY), and spontaneously hypertensive (SHR) rats underwent bilateral OVX or sham surgery (SHX) and were fed a normal salt diet (0.5% NaCl) for 14 wk. Systolic blood pressures were measured every 2 wk and were not significantly different between OVX and SHX for DR, WKY, and SHR groups. However, at the end of 14 wk of normal salt diet, hypertension developed in DS OVX but not SHX rats (160±3 vs. 136±3 mm Hg; P<0.05). Hypertension also developed in DS OVX rats pair-fed a normal salt diet (166±7 mm Hg). Development of hypertension in DS OVX rats was prevented by estrogen replacement (132±3 mm Hg), AT1 receptor blockade (119±3 mm Hg), or feeding a very low salt diet (0.1% NaCl; 129±4 mm Hg). Renal AT1 receptor protein expression was significantly elevated 2-fold in DS OVX relative to SHX rats and was prevented by estrogen replacement. These data strongly suggest that after OVX in salt-sensitive rats there is a lower threshold for the hypertensinogenic effect of salt that is linked to an activation of Ang II.
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    Krishnamurthi, K.; Verbalis, J. G.; Zheng, W.; Wu, Z.; Clerch, L. B.; Sandberg, K. Estrogen Regulates Angiotensin AT1 Receptor Expression via Cytosolic Proteins That Bind to the 52 Leader Sequence of the Receptor mRNA. Endocrinology 1999, 140 (11), 5435– 5438,  DOI: 10.1210/endo.140.11.7242
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    23
    Estrogen regulates angiotensin AT1 receptor expression via cytosolic proteins that bind to the 5' leader sequence of the receptor mRNA
    Krishnamurthi, Kamakshi; Verbalis, Joseph G.; Zheng, Wei; Wu, Zheng; Clerch, Linda B.; Sandberg, Kathryn
    Endocrinology (1999), 140 (11), 5435-5438CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)
    Two of the most highly recognized factors implicated in the pathogenesis of hypertension, atherosclerosis, congestive heart failure and assocd. cardiovascular disease are the renin-angiotensin system (RAS) and estrogen. A major effect of estrogen results from its influence on the RAS. β-Estradiol (E2) replacement in ovariectomized (OVX) rats significantly decreased type 1 angiotensin (AT1) receptor expression in the pituitary and adrenal, whereas it significantly increased receptor expression in the uterus when compared to OVX controls. Addnl. evidence demonstrated an important influence of estrogen on a recently discovered post-transcriptional mechanism for regulating expression of the AT1 receptor. This mechanism consists of cytosolic RNA binding proteins (BPs) that recognize the 5' leader sequence (5'LS) of the receptor mRNA. The activities of these 5'LS BPs were modulated by estrogen in an inverse manner to AT1 receptor regulation. Moreover, in vitro translation assays in wheat germ lysates suggested that the 5'LS BPs inhibited AT1 receptor translation. Our data therefore indicate that hormonal regulation of AT1 receptors involves modulation of 5'LS BPs by estrogen. These findings may in part account for the obsd. protective effects of estrogen on cardiovascular disease.
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    Ries, C.; Lucas, S.; Heim, R.; Birk, B.; Hartmann, R. W. Selective Aldosterone Synthase Inhibitors Reduce Aldosterone Formation in Vitro and in Vivo. J. Steroid Biochem. Mol. Biol. 2009, 116 (3–5), 121– 126,  DOI: 10.1016/j.jsbmb.2009.04.013
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    24
    Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo
    Ries, Christina; Lucas, Simon; Heim, Ralf; Birk, Barbara; Hartmann, Rolf W.
    Journal of Steroid Biochemistry and Molecular Biology (2009), 116 (3-5), 121-126CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
    Aldosterone plays a crucial role in salt and water homeostasis but in case of pathol. increased plasma aldosterone levels it is also involved in the development and the progression of severe cardiovascular diseases like heart failure and myocardial fibrosis. For the treatment of these diseases we propose inhibition of the aldosterone forming enzyme CYP11B2 as a new pharmacol. strategy. We recently developed in vitro highly potent and selective inhibitors of human CYP11B2, but the evidence of their in vivo activity is still missing. For this purpose, rat aldosterone synthase gene was cloned and expressed in V79MZ cells to establish a new screening assay for the identification of "rat-active" substances. Compds. from the class of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones showed a moderate inhibitory effect (65% at 2 μM) on rat CYP11B2 in vitro. Furthermore, it diminished the conversion of deoxycorticosterone to aldosterone in rat adrenals and significantly reduced plasma aldosterone levels in vivo.
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    Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem. 2014, 57 (19), 7874– 7887,  DOI: 10.1021/jm5006463
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    Polypharmacology: Challenges and Opportunities in Drug Discovery
    Anighoro, Andrew; Bajorath, Jurgen; Rastelli, Giulio
    Journal of Medicinal Chemistry (2014), 57 (19), 7874-7887CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biol. target, shares the spotlight with an emerging and alternative polypharmacol. approach. Polypharmacol. suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this review, we will compare advantages and disadvantages of multitarget vs. combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multitarget drugs.
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    Pinzi, L.; Tinivella, A.; Gagliardelli, L.; Beneventano, D.; Rastelli, G. LigAdvisor: A Versatile and User-Friendly Web-Platform for Drug Design. Nucleic Acids Res. 2021, 49 (W1), W326– W335,  DOI: 10.1093/nar/gkab385
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    LigAdvisor: a versatile and user-friendly web-platform for drug design
    Pinzi, Luca; Tinivella, Annachiara; Gagliardelli, Luca; Beneventano, Domenico; Rastelli, Giulio
    Nucleic Acids Research (2021), 49 (W1), W326-W335CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    Although several tools facilitating in silico drug design are available, their results are usually difficult to integrate with publicly available information or require further processing to be fully exploited. The rational design of multi-target ligands (polypharmacol.) and the repositioning of known drugs towards unmet therapeutic needs (drug repurposing) have raised increasing attention in drug discovery, although they usually require careful planning of tailored drug design strategies. Computational tools and data-driven approaches can help to reveal novel valuable opportunities in these contexts, as they enable to efficiently mine publicly available chem., biol., clin., and disease-related data. Based on these premises, we developed LigAdvisor, a data-driven webserver which integrates information reported in DrugBank, Protein Data Bank, UniProt, Clin. Trials and Therapeutic Target Database into an intuitive platform, to facilitate drug discovery tasks as drug repurposing, polypharmacol., target fishing and profiling. As designed, LigAdvisor enables easy integration of similarity estn. results with clin. data, thereby allowing a more efficient exploitation of information in different drug discovery contexts. Users can also develop customizable drug design tasks on their own mols., by means of ligand- and target-based search modes, and download their results.
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    Ankley, G. T.; Kahl, M. D.; Jensen, K. M.; Hornung, M. W.; Korte, J. J.; Makynen, E. A.; Leino, R. L. Evaluation of the Aromatase Inhibitor Fadrozole in a Short-Term Reproduction Assay with the Fathead Minnow (Pimephales Promelas). Toxicol. Sci. 2002, 67 (1), 121– 130,  DOI: 10.1093/toxsci/67.1.121
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    Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas)
    Ankley, Gerald T.; Kahl, Michael D.; Jensen, Kathleen M.; Hornung, Michael W.; Korte, Joseph J.; Makynen, Elizabeth A.; Leino, Richard L.
    Toxicological Sciences (2002), 67 (1), 121-130CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)
    Cytochrome P 450 aromatase (CYP19) is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such as β-estradiol (E2). The objective of this study was to assess effects of the CYP19 inhibitor fadrozole on fathead minnow (Pimephales promelas) reproductive endocrinol. and physiol. in a short-term reprodn. assay proposed for identifying specific classes of endocrine-disrupting chems. A concn.-dependent redn. in fecundity was obsd. in fish exposed for 21 days to water concns. of fadrozole ranging from 2 to 50 μg/l. Consistent with the expected mechanism of action, there was a significant inhibition of brain aromatase activity in both male and female fathead minnows exposed to fadrozole. In females, this inhibition was accompanied by a concn.-dependent decrease in plasma E2 and vitellogenin concns.; the latter observation is consistent with the fact that activation of the estrogen receptor by E2 initiates hepatic vitellogenin prodn. in oviparous vertebrates. Histol. assessment of ovaries from females exposed to fadrozole indicated a decrease in mature oocytes and an increase in preovulatory atretic follicles. Exposure of male fathead minnows to fadrozole significantly increased plasma concns. of the androgens testosterone (T) and 11-ketotestosterone (KT) and resulted in a marked accumulation of sperm in the tests. Results of this study indicate that the proposed fathead minnow assay should effectively identify test chems. as potential aromatase inhibitors, both in the context of their reproductive toxicity and the specific mechanism of action. These results also should be of utility in assessing the potential ecol. risk of CYP19 inhibitors, in particular in the context of relating alterations in subcellular indicators of endocrine function (changes in steroids, proteins) to adverse consequences in the whole organism.
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    Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager, A. Fadrozole Hydrochloride: A Potent, Selective, Nonsteroidal Inhibitor of Aromatase for the Treatment of Estrogen-Dependent Disease. J. Med. Chem. 1991, 34 (2), 725– 736,  DOI: 10.1021/jm00106a038
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    Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease
    Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager, A.
    Journal of Medicinal Chemistry (1991), 34 (2), 725-36CODEN: JMCMAR; ISSN:0022-2623.
    The prepn. of 5-phenyl-5,6,7,8-tetrahydroimidazopyridine derivs. I (R = cyano, Br, CH2OH, Me, CO2H, CO2Et) and their evaluation as inhibitors for aromatase and estrogen prodn. was described; the most potent aromatase inhibitor was (+)-I (R = cyano), i.e. fadrozole (CGS 16949A). The mol. structure-activity relationship was discussed.
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    Ménard, J.; Pascoe, L. Can the Dextroenantiomer of the Aromatase Inhibitor Fadrozole Be Useful for Clinical Investigation of Aldosterone-Synthase Inhibition?. J. Hypertens. 2006, 24 (6), 993– 997,  DOI: 10.1097/01.hjh.0000226183.98439.b3
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    Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?
    Menard, Joel; Pascoe, Leigh
    Journal of Hypertension (2006), 24 (6), 993-997CODEN: JOHYD3; ISSN:0263-6352. (Lippincott Williams & Wilkins)
    A review. The beneficial effects of spironolactone, eplerenone, amiloride, and potassium in preventing cardiovascular damage in various exptl. models of salt-induced hypertension can be dissocd. from blood pressure effects, and have drawn attention to the direct genomic and non-genomic actions of aldosterone at the level of the vessels, the heart, and the kidneys. Exposure to endogenous aldosterone could be decreased by direct and specific aldosterone-synthase inhibition. FAD 286A, the dextroenantiomer of the aromatase inhibitor fadrozole, might be a 1st candidate to investigate in humans, the physiol. impact and therapeutic properties of aldosterone-synthase inhibition, esp. in various forms of primary aldosteronism.
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    Smith, I. E.; Norton, A. Fadrozole and Letrozole in Advanced Breast Cancer: Clinical and Biochemical Effects. Breast Cancer Res. Treat. 1998, 49 (S1), S67– S71,  DOI: 10.1023/A:1006005024377
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    Fadrozole and letrozole in advanced breast cancer: clinical and biochemical effects
    Smith, Ian E.; Norton, Alison
    Breast Cancer Research and Treatment (1998), 49 (Suppl. 1), S67-S71CODEN: BCTRD6; ISSN:0167-6806. (Kluwer Academic Publishers)
    A review with 18 refs.
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    Lamberts, S. W. J.; Bruining, H. A.; Marzouk, H.; Zuiderwijk, J.; Uitterlinden, P.; Blijd, J. J.; Hackeng, W. H. L.; Jong, F. H. D. The New Aromatase Inhibitor CGS-16949A SuppressesAldosterone and Cortisol Production by Human Adrenal Cells in Vitro. J. Clin. Endocrinol. Metab. 1989, 69 (4), 896– 901,  DOI: 10.1210/jcem-69-4-896
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    The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro
    Lamberts, S. W. J.; Bruining, H. A.; Marzouk, H.; Zuiderwijk, J.; Uitterlinden, P.; Blijd, J. J.; Hackeng, W. H. L.; De Jong, F. H.
    Journal of Clinical Endocrinology and Metabolism (1989), 69 (4), 896-901CODEN: JCEMAZ; ISSN:0021-972X.
    CGS-16949A is a new orally active nonsteroidal aromatase inhibitor which is more than 100-fold more potent than aminoglutethimide. This compd. is an imidazole deriv., and therefore, its possible effect on cytochrome P 450-dependent enzyme activities in the adrenal gland was evaluated. In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10-7-10-6M is a potent 11β-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concn. of metyrapone (IC50 for both compds., 10-7-5 × 10-7M). Etomidate was a more potent 11 β-hydroxylase inhibitor (IC50, ∼10-8M), while 10-7-10-6M ketoconazole caused (via 17α-hydroxylase inhibition) a similar inhibition of cortisol release as 10-7M CGS-16949A (IC50, 10-7-5 × 10-5M). The 11β-hydroxylase inhibition by CGS-16949A was accompanied by a dose-dependent increase in the release of precursor steroids by the adrenocortical cells in vitro, including deoxycortisol, 17-hydroxyprogesterone, and androstenedione. Aldosterone release was suppressed 50% by 10-8M CGS-16949A, while the IC50 for cortisol in the same cells was 10-7M. Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also suppressed by CGS-16949A. It is concluded that the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11β-hydroxylase which is equipotent to metyrapone. At present it is unclear whether the compd. at the dose that causes complete aromatase inhibition in vivo also affects stress-induced cortisol release in man. Also, CGS-16949A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10-9M) and on a tumorous aldosterone secretion. CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.
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    Hu, Q.; Yin, L.; Hartmann, R. W. Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases: Miniperspective. J. Med. Chem. 2014, 57 (12), 5011– 5022,  DOI: 10.1021/jm401430e
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    Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases
    Hu, Qingzhong; Yin, Lina; Hartmann, Rolf W.
    Journal of Medicinal Chemistry (2014), 57 (12), 5011-5022CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and vol., recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathol. circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clin. trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.
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  33. 33
    Roumen, L.; Peeters, J. W.; Emmen, J. M. A.; Beugels, I. P. E.; Custers, E. M. G.; De Gooyer, M.; Plate, R.; Pieterse, K.; Hilbers, P. A. J.; Smits, J. F. M.; Vekemans, J. A. J.; Leysen, D.; Ottenheijm, H. C. J.; Janssen, H. M.; Hermans, J. J. R. Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-Imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2). J. Med. Chem. 2010, 53 (4), 1712– 1725,  DOI: 10.1021/jm901356d
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    Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
    Roumen, Luc; Peeters, Joris W.; Emmen, Judith M. A.; Beugels, Ilona P. E.; Custers, Erica M. G.; de Gooyer, Marcel; Plate, Ralf; Pieterse, Koen; Hilbers, Peter A. J.; Smits, Jos F. M.; Vekemans, Jef A. J.; Leysen, Dirk; Ottenheijm, Harry C. J.; Janssen, Henk M.; Hermans, J. J. Rob
    Journal of Medicinal Chemistry (2010), 53 (4), 1712-1725CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, three-dimensional modeling of CYP11B2 was used to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole (I) as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with the novel lead MOERAS115 (II) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (vs. CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC50 for CYP11B2 6.0 nM, selectivity 19.8). Mol. docking of the inhibitors in the models enabled the generation of posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.
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  34. 34
    Weldon, S. M.; Cerny, M. A.; Gueneva-Boucheva, K.; Cogan, D.; Guo, X.; Moss, N.; Parmentier, J.-H.; Richman, J. R.; Reinhart, G. A.; Brown, N. F. Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2016, 359 (1), 142– 150,  DOI: 10.1124/jpet.116.236463
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    Selectivity of BI 689648, a novel, highly selective aldosterone synthase inhibitor: comparison with FAD286 and LCI699 in nonhuman primates
    Weldon, Steven M.; Cerny, Matthew A.; Gueneva-Boucheva, Kristina; Cogan, Derek; Guo, Xin; Moss, Neil; Parmentier, Jean-Hugues; Richman, Jeremy R.; Reinhart, Glenn A.; Brown, Nicholas F.
    Journal of Pharmacology and Experimental Therapeutics (2016), 359 (1), 142-150CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
    The mineralocorticoid aldosterone is an important regulator of blood pressure, vol., and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis assocd. with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the prodn. of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathol. effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared with human (63%). Using cynomolgus (cyno) monkey-based models, we identified BI 689648 [6-(5-methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide], a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nMagainst AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 [4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile] (3 nM AS; 90 nM CS; 40-fold) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile) (10 nM AS; 80 nM CS; 8-fold). After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concn. of ∼500 nM. For in vivo profiling we used an ACTH-challenge model in which BI 689648 was.20-fold more selective compared with FAD286 and LCI699. Because both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective mols. to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward toward developing ASIs with greater potential for clin. success in cardiometabolic diseases.
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    Matore, B. W.; Banjare, P.; Singh, J.; Roy, P. P. In Silico Selectivity Modeling of Pyridine and Pyrimidine Based CYP11B1 and CYP11B2 Inhibitors: A Case Study. J. Mol. Graph. Model. 2022, 116, 108238  DOI: 10.1016/j.jmgm.2022.108238
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    In silico selectivity modeling of pyridine and pyrimidine based CYP11B1 and CYP11B2 inhibitors: A case study
    Matore, Balaji Wamanrao; Banjare, Purusottam; Singh, Jagadish; Roy, Partha Pratim
    Journal of Molecular Graphics & Modelling (2022), 116 (), 108238CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
    Design of selective drug candidates for highly structural similar targets is a challenging task for researchers. The main objective of this study was to explore the selectivity modeling of pyridine and pyrimidine scaffold towards the highly homologous targets CYP11B1 and CYP11B2 enzymes by in silico (Mol. docking and QSAR) approaches. In this regard, a big dataset (n = 228) of CYP11B1 and CYP11B2 inhibitors were gathered and classified based on heterocyclic ring and the exhaustive anal. was carried out for pyridine and pyrimidinescaffolds. The LibDock algorithm was used to explore the binding pattern, screening, and identify the structural feature responsible for the selectivity of the ligands towards the studied targets. Finally, QSAR anal. was done to explore the correlation between various binding parameters and structural features responsible for the inhibitory activity and selectivity of the ligands in a quant. way. The docking and QSAR anal. clearly revealed and distinguished the importance of structural features, functional groups attached for CYP11B2 and CYP11B1 selectivity for pyridine and pyrimidine analogs. Addnl., the docking anal. highlighted the differentiating amino acids residues for selectivity for ligands for each of the enzymes. The results obtained from this research work will be helpful in designing the selective CYP11B1/CYP11B2 inhibitors.
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    Baumann, M.; Baxendale, I. R. Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multicomponent Reactions. Org. Lett. 2014, 16 (23), 6076– 6079,  DOI: 10.1021/ol502845h
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    Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multi-component Reactions
    Baumann, Marcus; Baxendale, Ian R.
    Organic Letters (2014), 16 (23), 6076-6079CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    The synthesis of diversely functionalized thioimidazoles through a modern variant of the Marckwald reaction is presented. This new protocol utilizes unprotected carbohydrates as well as simple amine salts as sustainable and biorenewable starting materials. Importantly it was discovered that a bifurcated reaction pathway results from using aldoses and ketoses resp., yielding distinct reaction products in a highly selective manner.
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    Baumann, M.; Baxendale, I. R. A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives: A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives. Eur. J. Org. Chem. 2017, 2017 (44), 6518– 6524,  DOI: 10.1002/ejoc.201700833
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    A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives
    Baumann, Marcus; Baxendale, Ian R.
    European Journal of Organic Chemistry (2017), 2017 (44), 6518-6524CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented, which generates the corresponding imidazole derivs. I (R = C6H5, 4-BrC6H4, 2,6-F2C6H3,etc.) in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of the thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide byproducts as obsd. in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters II (R = C6H5, 4-BrC6H4, 2,6-F2C6H3, etc.; R1 = Me, Et, i-Pr, CH2CF3) representing new derivs. of the known analgesic etomidate through an efficient one-pot Corey-Gilman-Ganem oxidn. procedure.
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    Baumann, M.; Baxendale, I. R. A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles. Bioorg. Med. Chem. 2017, 25 (23), 6218– 6223,  DOI: 10.1016/j.bmc.2017.01.022
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    A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles
    Baumann, Marcus; Baxendale, Ian R.
    Bioorganic & Medicinal Chemistry (2017), 25 (23), 6218-6223CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethanesulfenyl chloride reagent including its in-line quenching in order to eliminate malodorous and corrosive byproducts. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole was safely prepd. allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.
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    Maligres, P. E.; Waters, M. S.; Weissman, S. A.; McWilliams, J. C.; Lewis, S.; Cowen, J.; Reamer, R. A.; Volante, R. P.; Reider, P. J.; Askin, D. Preparation of a Clinically Investigated Ras Farnesyl Transferase Inhibitor. J. Heterocycl. Chem. 2003, 40 (2), 229– 241,  DOI: 10.1002/jhet.5570400206
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    Preparation of a clinically investigated ras farnesyl transferase inhibitor
    Maligres, Peter E.; Waters, Marjorie S.; Weissman, Steven A.; McWilliams, J. Christopher; Lewis, Stephanie; Cowen, Jennifer; Reamer, Robert A.; Volante, R. P.; Reider, Paul J.; Askin, David
    Journal of Heterocyclic Chemistry (2003), 40 (2), 229-241CODEN: JHTCAD; ISSN:0022-152X. (HeteroCorporation)
    The synthesis of ras farnesyl-protein transferase inhibitor I is described on a multi-kilogram scale. Retrosynthetic anal. reveals chloromethylimidazole II and a piperazinone III as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure was developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodol. was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prep. the arylpiperazinone fragment III.
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    Ashburn, T. T.; Thor, K. B. Drug Repositioning: Identifying and Developing New Uses for Existing Drugs. Nat. Rev. Drug Discovery 2004, 3 (8), 673– 683,  DOI: 10.1038/nrd1468
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    Drug repositioning: identifying and developing new uses for existing drugs
    Ashburn, Ted T.; Thor, Karl B.
    Nature Reviews Drug Discovery (2004), 3 (8), 673-683CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of prodn. to biotechnol. companies. More and more companies are scanning the existing pharmacopeia for repositioning candidates, and the no. of repositioning success stories is increasing.
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    March-Vila, E.; Pinzi, L.; Sturm, N.; Tinivella, A.; Engkvist, O.; Chen, H.; Rastelli, G. On the Integration of In Silico Drug Design Methods for Drug Repurposing. Front. Pharmacol. 2017, 8, 298,  DOI: 10.3389/fphar.2017.00298
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    On the integration of in silico drug design methods for drug repurposing
    March-Vila, Eric; Pinzi, Luca; Sturm, Noe; Tinivella, Annachiara; Engkvist, Ola; Chen, Hongming; Rastelli, Giulio
    Frontiers in Pharmacology (2017), 8 (), 298/1-298/7CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
    Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A no. of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease assocns.
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    Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074– D1082,  DOI: 10.1093/nar/gkx1037
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    DrugBank 5.0: a major update to the DrugBank database for 2018
    Wishart, David S.; Feunang, Yannick D.; Guo, An C.; Lo, Elvis J.; Marcu, Ana; Grant, Jason R.; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael
    Nucleic Acids Research (2018), 46 (D1), D1074-D1082CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    DrugBank is a web-enabled database contg. comprehensivemol. information about drugs, their mechanisms, their interactions and their targets. First described in 2006, Drug- Bank has continued to evolve over the past 12 years in response to marked improvements to web stds. and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total no. of investigational drugs in the database has grown by almost 300%, the no. of drug-drug interactions has grown by nearly 600% and the no. of SNP-assocd. drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoproteomics). New data have also been added on the status of hundreds of newdrug clin. trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacol. research, pharmaceutical science and drug education.
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    Berman, H. M. The Protein Data Bank. Nucleic Acids Res. 2000, 28 (1), 235– 242,  DOI: 10.1093/nar/28.1.235
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    The Protein Data Bank
    Berman, Helen M.; Westbrook, John; Feng, Zukang; Gilliland, Gary; Bhat, T. N.; Weissig, Helge; Shindyalov, Ilya N.; Bourne, Philip E.
    Nucleic Acids Research (2000), 28 (1), 235-242CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The Protein Data Bank (PDB; http://www.rcsb.org/pdb/)is the single worldwide archive of structural data of biol. macromols. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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    Buzdar, A. U.; Robertson, J. F. R.; Eiermann, W.; Nabholtz, J.-M. An Overview of the Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors Anastrozole, Letrozole, and Exemestane. Cancer 2002, 95 (9), 2006– 2016,  DOI: 10.1002/cncr.10908
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    An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane
    Buzdar, Aman U.; Robertson, John F. R.; Eiermann, Wolfgang; Nabholtz, Jean-Marc
    Cancer (New York, NY, United States) (2002), 95 (9), 2006-2016CODEN: CANCAR; ISSN:0008-543X. (John Wiley & Sons, Inc.)
    A review. The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clin. benefit. Because these agents ultimately may be administered for periods of up to 5 yr in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacol. profiles. In the absence of data from direct clin. comparisons, the published literature was reviewed for the clin. pharmacol., pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. At clin. administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 h, 2-4 days, and 27 h, resp. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. All three AIs demonstrated clin. efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clin. significance of these differences remains to be elucidated.
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    Grimm, S. W.; Dyroff, M. C. Inhibition of Human Drug Metabolizing Cytochromes P450 by Anastrozole, a Potent and Selective Inhibitor of Aromatase. Drug Metab. Dispos. Biol. Fate Chem. 1997, 25 (5), 598– 602
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    Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase
    Grimm S W; Dyroff M C
    Drug metabolism and disposition: the biological fate of chemicals (1997), 25 (5), 598-602 ISSN:0090-9556.
    Anastrozole (2,2'[5(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]- bis(2-methylproprionitrile)) is a potent third-generation inhibitor of aromatase, currently marketed as a treatment for postmenopausal women with advanced breast cancer. While its potency and selectivity for inhibition of estrogen synthesis has been established in both preclinical and clinical studies, this study used in vitro methods to examine the effects of anastrozole on several drug metabolizing CYP enzymes found in human liver. Human liver microsomes were co-incubated with anastrozole and probe substrates for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6 (dextromethorphan), and CYP3A (nifedipine). The formation of the CYP-specific metabolites following co-incubation with various anastrozole concentrations was determined to establish IC50 and Ki values for these enzymes. While anastrozole did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 microM, this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with Ki values of 8, 10, and 10 microM, respectively. Dixon plots used to determine the Ki values for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic, indicating additional lower affinity Ki values. Major metabolites of anastrozole did not retain the ability to inhibit the metabolism of nifedipine (CYP3A). The results of this study indicate that, although anastrozole can inhibit CYP1A2, 2C9, and 3A-mediated catalytic activities, this compound would not be expected to cause clinically significant interactions with other CYP-metabolized drugs at physiologically relevant concentrations achieved during therapy with Arimidex (Zeneca, Ltd., Macclesfield, UK) 1-mg.
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    Gobbi, S.; Rampa, A.; Belluti, F.; Bisi, A. Nonsteroidal Aromatase Inhibitors for the Treatment of Breast Cancer: An Update. Anticancer Agents Med. Chem. 2014, 14 (1), 54– 65,  DOI: 10.2174/18715206113139990306
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    Nonsteroidal aromatase inhibitors for the treatment of breast cancer: an update
    Gobbi Silvia; Rampa Angela; Belluti Federica; Bisi Alessandra
    Anti-cancer agents in medicinal chemistry (2014), 14 (1), 54-65 ISSN:.
    Estrogens are known to be important in breast cancer growth in both pre- and post-menopausal women. Although circulating estrogen concentrations are very low after menopause, peripheral tissues generate sufficient concentrations to stimulate tumor growth. As aromatase is the rate-limiting enzyme in estrogen biosynthesis, inhibitors of this enzyme represent effective targeted therapy for breast cancer. Three compounds are now FDA approved and have become the first-choice endocrine drugs for postmenopausal breast cancer patients, since they are associated with superior activity and better general tolerability when compared with the estrogen receptor modulator tamoxifen. Nevertheless, some questions concerning the use of aromatase inhibitors for the treatment of breast cancer still need to be addressed, mainly related to their side-effects and the development of resistance, making research in this field still appealing. Many research groups, including our own, are still dealing with the search of new compounds that possess aromatase inhibitory properties. In this review an update of the latest achievements in the field of nonsteroidal aromatase inhibitors will be given.
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    Rotstein, D. M.; Kertesz, D. J.; Walker, K. A. M.; Swinney, D. C. Stereoisomers of Ketoconazole: Preparation and Biological Activity. J. Med. Chem. 1992, 35 (15), 2818– 2825,  DOI: 10.1021/jm00093a015
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    Stereoisomers of ketoconazole: preparation and biological activity
    Rotstein, David M.; Kertesz, Denis J.; Walker, Keith A. M.; Swinney, David C.
    Journal of Medicinal Chemistry (1992), 35 (15), 2818-25CODEN: JMCMAR; ISSN:0022-2623.
    The four stereoisomers of the antifungal agent ketoconazole, (2S,4R)-, (2R,4R)-, (2R,4S)-, and (2S,4S)-(imidazolylmethyl)phenyl{[(acetylpiperazinyl)phenoxy]methyl}dioxolanes I, were prepd. and evaluated for their selectivity in inhibiting a no. of cytochrome P 450 enzymes. Thus, (bromomethyl)phenyldioxolanes II condensed with 4-(N-acetylpiperazino)phenol and imidazole to give I. II were prepd. by bromination of 2',4'-dichloroacetophenone followed by reaction with (S)- and (R)-solketal tosylate. Large differences in selectivity among the isomers were obsd. for inhibition of the cytochromes P 450 involved in steroid biosynthesis, whereas little difference was obsd. for inhibition of those assocd. with hepatic drug metab. The cis-(2S,4R) and trans-(2R,4R) isomers are equipotent in inhibiting corticoid 11β-hydroxylase and much more effective than their antipodes. Little selectivity was obsd. for inhibition of cholesterol side chain cleavage or xenobiotic hydroxylases. These data indicate that the affinity of azoles for cytochrome P 450 enzymes involved in steroid synthesis is high dependent on the stereochem. of the entire mol., whereas binding to drug metabolizing enzymes is a less selective process.
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    Fleseriu, M.; Castinetti, F. Updates on the Role of Adrenal Steroidogenesis Inhibitors in Cushing’s Syndrome: A Focus on Novel Therapies. Pituitary 2016, 19 (6), 643– 653,  DOI: 10.1007/s11102-016-0742-1
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    Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies
    Fleseriu, Maria; Castinetti, Frederic
    Pituitary (2016), 19 (6), 643-653CODEN: PITUF9; ISSN:1386-341X. (Springer)
    A review. Purpose: Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approx. 25% of patients, esp. those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatol. CS is rare overall, and clin. studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. Methods: We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. Results: Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). Conclusions: The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.
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    Brixius-Anderko, S.; Scott, E. E. Structure of Human Cortisol-Producing Cytochrome P450 11B1 Bound to the Breast Cancer Drug Fadrozole Provides Insights for Drug Design. J. Biol. Chem. 2019, 294 (2), 453– 460,  DOI: 10.1074/jbc.RA118.006214
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    49
    Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design
    Brixius-Anderko, Simone; Scott, Emily E.
    Journal of Biological Chemistry (2019), 294 (2), 453-460CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Human cytochrome P 450 11B1 (CYP11B1) is responsible for the final step generating the steroid hormone cortisol, which controls stress and immune responses and glucose homeostasis. CYP11B1 is a promising drug target to manage Cushing's disease, a disorder arising from excessive cortisol prodn. However, the design of selective inhibitors has been hampered because structural information for CYP11B1 is unavailable and the enzyme has high amino acid sequence identity (93%) to a closely related enzyme, the aldosterone-producing CYP11B2. Here the authors report the x-ray crystal structure of human CYP11B1 (at 2.1 Å resoln.) in complex with fadrozole, a racemic compd. normally used to treat breast cancer by inhibiting estrogen-producing CYP19A1. Comparison of fadrozole-bound CYP11B1 with fadrozole-bound CYP11B2 revealed that despite conservation of the active-site residues, the overall structures and active sites had structural rearrangements consistent with distinct protein functions and inhibition. Whereas fadrozole binds to both CYP11B enzymes by coordinating the heme iron, CYP11B2 binds to the R enantiomer of fadrozole, and CYP11B1 binds to the S enantiomer, each with distinct orientations and interactions. These results provide insights into the cross-reactivity of drugs across multiple steroidogenic cytochrome P 450 enzymes, provide a structural basis for understanding human steroidogenesis, and pave the way for the design of more selective inhibitors of each human CYP11B enzyme.
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    Brixius-Anderko, S.; Scott, E. E. Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design. Hypertension 2021, 78 (3), 751– 759,  DOI: 10.1161/HYPERTENSIONAHA.121.17615
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    50
    Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design
    Brixius-Anderko, Simone; Scott, Emily E.
    Hypertension (2021), 78 (3), 751-759CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
    Primary aldosteronism, the major form of secondary hypertension, develops due to excess steroid hormone aldosterone produced by aldosterone synthase, also known as cytochrome P 450 11B2. CYP11B2 is 93% identical to cortisol-producing CYP11B1, which makes it difficult to design selective drugs. LCI699 (Osilodrostat, Isturisa) was initially developed as a CYP11B2 inhibitor but due to poor selectivity was recently repurposed as the first Food and Drug Administration-approved drug for CYP11B1-mediated Cushing disease. Thus, there is still no effective therapeutic option targeting CYP11B2 for primary aldosteronism. Using a structure/function approach, aspects of LCI699 interaction with CYP11B2 were examd. to facilitate the design of more selective inhibitors. LCI699 effectively binds and inhibits CYP11B2. To det. the structural basis for this interaction, X-ray crystallog. was used to solve the structure of CYP11B2 bound to LCI699. LCI699 binds in the active site with its imidazole nitrogen coordinating the heme iron. LCI699 binding was compared with that of its analog fadrozole to both CYP11B enzymes. Comparison with the CYP11B1 structure reveals distinct CYP11B active site architectures which can be exploited to directed drug design. Exploiting structural differences between the CYP11B enzymes will promote the design of therapeutics for the treatment of primary aldosteronism targeting CYP11B2 while reducing undesirable side effects due to off-target CYP11B1 inhibition.
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    Strushkevich, N.; Gilep, A. A.; Shen, L.; Arrowsmith, C. H.; Edwards, A. M.; Usanov, S. A.; Park, H.-W. Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition. Mol. Endocrinol. 2013, 27 (2), 315– 324,  DOI: 10.1210/me.2012-1287
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    Structural insights into aldosterone synthase substrate specificity and targeted inhibition
    Strushkevich, Natallia; Gilep, Andrei A.; Shen, Limin; Arrowsmith, Cheryl H.; Edwards, Aled M.; Usanov, Sergey A.; Park, Hee-Won
    Molecular Endocrinology (2013), 27 (2), 315-324CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)
    Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure. Excess aldosterone levels can arise from dysregulation of the renin-angiotensin-aldosterone system and are implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (cytochrome P 450 11B2, CYP11B2) is the sole enzyme responsible for the prodn. of aldosterone in humans. Blocking of aldosterone synthesis by mediating aldosterone synthase activity is thus a recently emerging pharmacol. therapy for hypertension, yet a lack of structural information has limited this approach. Here, we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone and an inhibitor fadrozole. The structures reveal a hydrophobic cavity with specific features assocd. with corticosteroid recognition. The substrate binding mode, along with biochem. data, explains the high 11β-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation. The low processivity of aldosterone synthase with a high extent of intermediates release might be one of the mechanisms of controlled aldosterone prodn. from deoxycorticosterone. Although the active site pocket is lined by identical residues between CYP11B isoforms, most of the divergent residues that confer addnl. 18-oxidase activity of aldosterone synthase are located in the I-helix (vicinity of the O2 activation path) and loops around the H-helix (affecting an egress channel closure required for retaining intermediates in the active site). This intrinsic flexibility is also reflected in isoform-selective inhibitor binding. Fadrozole binds to aldosterone synthase in the R-configuration, using part of the active site cavity pointing toward the egress channel. The structural organization of aldosterone synthase provides crit. insights into the mol. mechanism of catalysis and enables rational design of more specific antihypertensive agents.
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    Pinzi, L.; Rastelli, G. Identification of Target Associations for Polypharmacology from Analysis of Crystallographic Ligands of the Protein Data Bank. J. Chem. Inf. Model. 2020, 60 (1), 372– 390,  DOI: 10.1021/acs.jcim.9b00821
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    Identification of Target Associations for Polypharmacology from Analysis of Crystallographic Ligands of the Protein Data Bank
    Pinzi, Luca; Rastelli, Giulio
    Journal of Chemical Information and Modeling (2020), 60 (1), 372-390CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    The design of a chem. entity that potently and selectively binds to a biol. target of therapeutic relevance has dominated the scene of drug discovery so far. However, recent findings suggest that multi-target ligands may be endowed with superior efficacy and be less prone to drug resistance. The Protein Data Bank (PDB) provides exptl. validated structural information about targets and bound ligands. Therefore, it represents a valuable source of information to help identifying active sites, understanding pharmacophore requirements, designing novel ligands, and inferring structure-activity relationships. In this study, we performed a large-scale anal. of the PDB by integrating different ligand-based and structure-based approaches, with the aim of identifying promising target assocns. for polypharmacol. based on reported crystal structure information. First, the 2D and 3D similarity profiles of the crystallog. ligands were evaluated using different ligand-based methods. Then, activity data of pairs of similar ligands binding to different targets were inspected by comparing structural information with bioactivity annotations reported in the ChEMBL, BindingDB, BindingMOAD, and PDBbind databases. Afterward, extensive docking screenings of ligands in the identified cross-targets were made in order to validate and refine the ligand-based results. Finally, the therapeutic relevance of the identified target combinations for polypharmacol. was evaluated from comparison with information on therapeutic targets reported in the Therapeutic Target Database (TTD). The results led to the identification of several target assocns. with high therapeutic potential for polypharmacol.
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    Hawkins, P. C. D.; Skillman, A. G.; Nicholls, A. Comparison of Shape-Matching and Docking as Virtual Screening Tools. J. Med. Chem. 2007, 50 (1), 74– 82,  DOI: 10.1021/jm0603365
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    Comparison of Shape-Matching and Docking as Virtual Screening Tools
    Hawkins, Paul C. D.; Skillman, A. Geoffrey; Nicholls, Anthony
    Journal of Medicinal Chemistry (2007), 50 (1), 74-82CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Ligand docking is a widely used approach in virtual screening. In recent years a large no. of publications have appeared in which docking tools are compared and evaluated for their effectiveness in virtual screening against a wide variety of protein targets. These studies have shown that the effectiveness of docking in virtual screening is highly variable due to a large no. of possible confounding factors. Another class of method that has shown promise in virtual screening is the shape-based, ligand-centric approach. Several direct comparisons of docking with the shape-based tool ROCS have been conducted using data sets from some of these recent docking publications. The results show that a shape-based, ligand-centric approach is more consistent than, and often superior to, the protein-centric approach taken by docking.
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  54. 54
    Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery. Nucleic Acids Res. 2012, 40 (D1), D1100– 1107,  DOI: 10.1093/nar/gkr777
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    ChEMBL: a large-scale bioactivity database for drug discovery
    Gaulton, Anna; Bellis, Louisa J.; Bento, A. Patricia; Chambers, Jon; Davies, Mark; Hersey, Anne; Light, Yvonne; McGlinchey, Shaun; Michalovich, David; Al-Lazikani, Bissan; Overington, John P.
    Nucleic Acids Research (2012), 40 (D1), D1100-D1107CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    ChEMBL is an Open Data database contg. binding, functional and ADMET information for a large no. of drug-like bioactive compds. These data are manually abstracted from the primary published literature on a regular basis, then further curated and standardized to maximize their quality and utility across a wide range of chem. biol. and drug-discovery research problems. Currently, the database contains 5.4 million bioactivity measurements for more than 1 million compds. and 5200 protein targets. Access is available through a web-based interface, data downloads and web services at: https://www.ebi.ac.uk/chembldb.
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  55. 55
    Gaulton, A.; Hersey, A.; Nowotka, M.; Bento, A. P.; Chambers, J.; Mendez, D.; Mutowo, P.; Atkinson, F.; Bellis, L. J.; Cibrián-Uhalte, E.; Davies, M.; Dedman, N.; Karlsson, A.; Magariños, M. P.; Overington, J. P.; Papadatos, G.; Smit, I.; Leach, A. R. The ChEMBL Database in 2017. Nucleic Acids Res. 2017, 45 (D1), D945– D954,  DOI: 10.1093/nar/gkw1074
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    The ChEMBL database in 2017
    Gaulton, Anna; Hersey, Anne; Nowotka, Micha-l; Bento, A. Patricia; Chambers, Jon; Mendez, David; Mutowo, Prudence; Atkinson, Francis; Bellis, Louisa J.; Cibrian-Uhalte, Elena; Davies, Mark; Dedman, Nathan; Karlsson, Anneli; Magarinos, Maria Paula; Overington, John P.; Papadatos, George; Smit, Ines; Leach, Andrew R.
    Nucleic Acids Research (2017), 45 (D1), D945-D954CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 and 2014 Nucleic Acids Research Database Issues. Since then, alongside the continued extn. of data from the medicinal chem. literature, new sources of bioactivity data have also been added to the database. These include: deposited data sets from neglected disease screening; crop protection data; drug metab. and disposition data and bioactivity data from patents. A no. of improvements and new features have also been incorporated. These include the annotation of assays and targets using ontologies, the inclusion of targets and indications for clin. candidates, addn. of metabolic pathways for drugs and calcn. of structural alerts. The ChEMBL data can be accessed via a web-interface, RDF distribution, data downloads and RESTful web-services.
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    Furet, P.; Batzl, C.; Bhatnagar, A.; Francotte, E.; Rihs, G.; Lang, M. Aromatase Inhibitors: Synthesis, Biological Activity, and Binding Mode of Azole-Type Compounds. J. Med. Chem. 1993, 36 (10), 1393– 1400,  DOI: 10.1021/jm00062a012
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    Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds
    Furet, P.; Batzl, C.; Bhatnagar, A.; Francotte, E.; Rihs, G.; Lang, M.
    Journal of Medicinal Chemistry (1993), 36 (10), 1393-400CODEN: JMCMAR; ISSN:0022-2623.
    The enantiomers of the potent nonsteroidal inhibitor of aromatase, fadrozole hydrochloride, I (R1 = 4-NCC6H4, R2 = H; R1 = H, R2 = 4-NCC6H4), have been sepd. and their abs. configuration detd. by x-ray crystallog. On the basis of a mol. modeling comparison of the active enantiomer I ((R1 = 4-NCC6H4, R2 = H) and one of the most potent steroidal inhibitors reported to date, (19R)-10-thiiranylestr-4-ene-3,17-dione, II, a model describing the relative binding modes of the azole-type and steroidal inhibitors of aromatase at the active site of the enzyme is proposed. It is suggested that the cyanophenyl moiety present in the most active azole inhibitors partially mimics the steroid backbone of the natural substrate for aromatase, androst-4-ene-3,17-dione. The synthesis and biol. testing of novel analogs of fadrozole used to define the accessible and nonaccessible vols. to ligands in the model of the active site of aromatase are reported. Thus, imidazole reacted with SOCl2 and 6-cyano-1-tetralone in CH2Cl2 to give imidazolylcyanotetralin III.
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    Meyers, K.; Cogan, D. A.; Burke, J.; Arenas, R.; Balestra, M.; Brown, N. F.; Chen, Z.; Cerny, M. A.; Clifford, H. E.; Colombo, F.; Fader, L.; Frederick, K. S.; Guo, X.; Goldberg, D.; Hornberger, K. R.; Kugler, S.; Lord, J.; Marshall, D. R.; Moss, N.; Parmentier, J.-H.; Richman, J. R.; Schmenk, J.; Weldon, S. M.; Yu, M.; Zhang, M. Dihydrobenzisoxazole-4-One Compounds Are Novel Selective Inhibitors of Aldosterone Synthase (CYP11B2) with in Vivo Activity. Bioorg. Med. Chem. Lett. 2018, 28 (5), 979– 984,  DOI: 10.1016/j.bmcl.2017.12.015
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    Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity
    Meyers, Kenneth; Cogan, Derek A.; Burke, Jennifer; Arenas, Raquel; Balestra, Michael; Brown, Nicholas F.; Cerny, Matthew A.; Clifford, Holly E.; Colombo, Federico; Fader, Lee; Frederick, Kosea S.; Guo, Xin; Hornberger, Keith R.; Kugler, Stanley; Lord, John; Marshall, Daniel R.; Moss, Neil; Richman, Jeremy R.; Schmenk, Jennifer; Weldon, Steven M.; Yu, Maolin; Zhang, Michael; Chen, Zhidong
    Bioorganic & Medicinal Chemistry Letters (2018), 28 (5), 979-984CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compds. are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a redn. of the isoxazole ring. While the enzyme responsible for the reductive metab. remains unknown, the rate of metab. could be attenuated by the addn. of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone prodn. without impacting plasma cortisol concns.
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    McGann, M. FRED Pose Prediction and Virtual Screening Accuracy. J. Chem. Inf. Model. 2011, 51 (3), 578– 596,  DOI: 10.1021/ci100436p
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    FRED Pose Prediction and Virtual Screening Accuracy
    McGann, Mark
    Journal of Chemical Information and Modeling (2011), 51 (3), 578-596CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Results of a previous docking study are reanalyzed and extended to include results from the docking program FRED and a detailed statistical anal. of both structure reprodn. and virtual screening results. FRED is run both in a traditional docking mode and in a hybrid mode that makes use of 16 the structure of a bound ligand in addn. to the protein structure to screen mols. This anal. shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next. Comparing methods, the difference in mean performance on DUD is found to be statistically significant (95% confidence) 61% of the time when using a global enrichment metric (AUC). Early enrichment metrics are found to have relatively poor statistical power, with 0.5% early enrichment only able to distinguish methods to 95% confidence 14% of the time.
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    Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural Basis for Androgen Specificity and Oestrogen Synthesis in Human Aromatase. Nature 2009, 457 (7226), 219– 223,  DOI: 10.1038/nature07614
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    Structural basis for androgen specificity and estrogen synthesis in human aromatase
    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter
    Nature (London, United Kingdom) (2009), 457 (7226), 219-223CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Aromatase cytochrome P 450 is the only enzyme in vertebrates known to catalyze the biosynthesis of all estrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for estrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P 450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to estrone, 17β-estradiol and 17β,16α-estriol, resp. The first two steps are C19-Me hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochem. mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P 450 and P 450 in hormone biosynthetic pathways to be crystd. so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione mol. snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The mol. basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.
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    Yin, L.; Hu, Q.; Hartmann, R. W. Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks. J. Med. Chem. 2013, 56 (2), 460– 470,  DOI: 10.1021/jm301408t
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    Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks
    Yin, Lina; Hu, Qingzhong; Hartmann, Rolf W.
    Journal of Medicinal Chemistry (2013), 56 (2), 460-470CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concns. of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, i.e., a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compds. 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, esp. compd. 3p (I), which exhibited IC50 values of 32 and 41 nM for CYP19 and CYP11B2, resp., and a high selectivity toward CYP17 and CYP11B1. This compd. is considered as a candidate for further evaluation in vivo.
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    Meredith, E. L.; Ksander, G.; Monovich, L. G.; Papillon, J. P. N.; Liu, Q.; Miranda, K.; Morris, P.; Rao, C.; Burgis, R.; Capparelli, M.; Hu, Q.-Y.; Singh, A.; Rigel, D. F.; Jeng, A. Y.; Beil, M.; Fu, F.; Hu, C.-W.; LaSala, D. Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors. ACS Med. Chem. Lett. 2013, 4 (12), 1203– 1207,  DOI: 10.1021/ml400324c
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    Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors
    Meredith, Erik L.; Ksander, Gary; Monovich, Lauren G.; Papillon, Julien P. N.; Liu, Qian; Miranda, Karl; Morris, Patrick; Rao, Chang; Burgis, Robin; Capparelli, Michael; Hu, Qi-Ying; Singh, Alok; Rigel, Dean F.; Jeng, Arco Y.; Beil, Michael; Fu, Fumin; Hu, Chii-Whei; LaSala, Daniel
    ACS Medicinal Chemistry Letters (2013), 4 (12), 1203-1207CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathol. such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clin. candidate I, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compd. I was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol prodn. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
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    Bochevarov, A. D.; Harder, E.; Hughes, T. F.; Greenwood, J. R.; Braden, D. A.; Philipp, D. M.; Rinaldo, D.; Halls, M. D.; Zhang, J.; Friesner, R. A. Jaguar: A High-performance Quantum Chemistry Software Program with Strengths in Life and Materials Sciences. Int. J. Quantum Chem. 2013, 113 (18), 2110– 2142,  DOI: 10.1002/qua.24481
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    Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences
    Bochevarov, Art D.; Harder, Edward; Hughes, Thomas F.; Greenwood, Jeremy R.; Braden, Dale A.; Philipp, Dean M.; Rinaldo, David; Halls, Mathew D.; Zhang, Jing; Friesner, Richard A.
    International Journal of Quantum Chemistry (2013), 113 (18), 2110-2142CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)
    A review. Jaguar is an ab initio quantum chem. program that specializes in fast electronic structure predictions for mol. systems of medium and large size. Jaguar focuses on computational methods with reasonable computational scaling with the size of the system, such as d. functional theory (DFT) and local second-order Moller-Plesset perturbation theory. The favorable scaling of the methods and the high efficiency of the program make it possible to conduct routine computations involving several thousand MOs. This performance is achieved through a utilization of the pseudospectral approxn. and several levels of parallelization. The speed advantages are beneficial for applying Jaguar in biomol. computational modeling. Addnl., owing to its superior wave function guess for transition-metal-contg. systems, Jaguar finds applications in inorg. and bioinorg. chem. The emphasis on larger systems and transition metal elements paves the way toward developing Jaguar for its use in materials science modeling. The article describes the historical and new features of Jaguar, such as improved parallelization of many modules, innovations in ab initio pKa prediction, and new semiempirical corrections for nondynamic correlation errors in DFT. Jaguar applications in drug discovery, materials science, force field parameterization, and other areas of computational research are reviewed. Timing benchmarks and other results obtained from the most recent Jaguar code are provided. The article concludes with a discussion of challenges and directions for future development of the program. © 2013 Wiley Periodicals, Inc.
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    Nelson, D. R.; Zeldin, D. C.; Hoffman, S. M.; Maltais, L. J.; Wain, H. M.; Nebert, D. W. Comparison of Cytochrome P450 (CYP) Genes from the Mouse and Human Genomes, Including Nomenclature Recommendations for Genes, Pseudogenes and Alternative-Splice Variants. Pharmacogenetics 2004, 14 (1), 1– 18,  DOI: 10.1097/00008571-200401000-00001
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    Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants
    Nelson, David R.; Zeldin, Darryl C.; Hoffman, Susan M. G.; Maltais, Lois J.; Wain, Hester M.; Nebert, Daniel W.
    Pharmacogenetics (2004), 14 (1), 1-18CODEN: PHMCEE; ISSN:0960-314X. (Lippincott Williams & Wilkins)
    A review. Completion of both the mouse and human genome sequences in the private and public sectors has prompted comparison between the two species at multiple levels. This review summarizes the cytochrome P 450 (CYP) gene superfamily. For the first time, we have the ability to compare complete sets of CYP genes from two mammals. Use of the mouse as a model mammal, and as a surrogate for human biol., assumes reasonable similarity between the two. It is therefore of interest to catalog the genetic similarities and differences, and to clarify the limits of extrapolation from mouse to human. Data-mining methods have been used to find all the mouse and human CYP sequences; this includes 102 putatively functional genes and 88 pseudogenes in the mouse, and 57 putatively functional genes and 58 pseudogenes in the human. Comparison is made between all these genes, esp. the seven main CYP gene clusters. The seven CYP clusters are greatly expanded in the mouse with 72 functional genes vs. only 27 in the human, while many pseudogenes are present; presumably this phenomenon will be seen in many other gene superfamily clusters. Complete identification of all pseudogene sequences is likely to be clin. important, because some of these highly similar exons can interfere with PCR-based genotyping assays. A naming procedure for each of four categories of CYP pseudogenes is proposed, and we encourage various gene nomenclature committees to consider seriously the adoption and application of this pseudogene nomenclature system.
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    Hare, S. H.; Harvey, A. J. mTOR Function and Therapeutic Targeting in Breast Cancer. Am. J. Cancer Res. 2017, 7 (3), 383– 404
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    mTOR function and therapeutic targeting in breast cancer
    Hare, Stephen H.; Harvey, Amanda J.
    American Journal of Cancer Research (2017), 7 (3), 383-404CODEN: AJCRFT; ISSN:2156-6976. (e-Century Publishing Corp.)
    The mTOR pathway was discovered in the late 1970s after the compd. and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy while mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer. This can involve mutations in mTOR itself but more commonly, in breast cancer, this is related to an increase in activity of ErbB family receptors or alterations and mutations of PI3K signaling. Rapamycin and its analogs (rapalogues) bind to the intercellular receptor FKBP12, and then predominantly inhibit mTORC1 signaling via an allosteric mechanism. Research has shown that inhibition of mTOR is a useful strategy in tackling cancers, with it acting to slow tumor growth and limit the spread of a cancer. Rapalogues have now made their way into the clinic with the rapalogue everolimus (RAD-001/Afinitor) approved for use in conjunction with exemestane, in post-menopausal breast cancer patients with advanced disease who are HER-2 neg. (normal expression), hormone receptor pos. and whose prior treatment with non-steroidal aromatase inhibitors has failed. Testing across multiple trials has proven that everolimus and other rapalogues are a viable way of treating certain types of cancer. However, rapalogues have shown some drawbacks both in research and clin., with their use often activating feedback pathways that counter their usefulness. As such, new types of inhibitors are being explored that work via different mechanisms, including inhibitors that are ATP competitive with mTOR and which act to perturb signaling from both mTOR complexes.
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    Hadizadeh, F.; Shafiee, A.; Kazemi, R.; Mohammadi, M. Synthesis of 4-(1-Phenylmethyl-5-Imidazolyl)-1,4-Dihydropyridines as Calcium Channel Antagonists; NISCAIR-CSIR: India, 2002; vol 41B (12), pp 2679– 2682.
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    Millet, R.; Domarkas, J.; Houssin, R.; Gilleron, P.; Goossens, J.-F.; Chavatte, P.; Logé, C.; Pommery, N.; Pommery, J.; Hénichart, J.-P. Potent and Selective Farnesyl Transferase Inhibitors. J. Med. Chem. 2004, 47 (27), 6812– 6820,  DOI: 10.1021/jm030502y
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    Potent and Selective Farnesyl Transferase Inhibitors
    Millet, Regis; Domarkas, Juozas; Houssin, Raymond; Gilleron, Pauline; Goossens, Jean-Francois; Chavatte, Philippe; Loge, Cedric; Pommery, Nicole; Pommery, Jean; Henichart, Jean-Pierre
    Journal of Medicinal Chemistry (2004), 47 (27), 6812-6820CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compds. possess an N-(4-piperidinyl)benzamide scaffold mimicking A1A2 residue. Extensive exploration of structure-activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC50 = 4.60 nM on isolated enzyme, EC50 = 20.0 nM for growth inhibition on a tumor cell line). The mol. docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
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    Berthold, M. R.; Cebron, N.; Dill, F.; Gabriel, T. R.; Kötter, T.; Meinl, T.; Ohl, P.; Sieb, C.; Thiel, K.; Wiswedel, B. KNIME: The Konstanz Information Miner. In Data Analysis, Machine Learning and Applications; Studies in Classification, Data Analysis, and Knowledge Organization; Preisach, C.; Burkhardt, H.; Schmidt-Thieme, L.; Decker, R., Eds.; Springer: Berlin, Heidelberg, 2008; pp 319– 326.
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  • Abstract

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    Figure 1

    Figure 1. Structures of (R)-fadrozole and (S)-fadrozole.

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    Figure 2

    Figure 2. Synthesized library of benzylimidazole derivatives.

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    Figure 3

    Figure 3. Predicted 3D ROCS-based alignments of compound X21 with (S)-fadrozole (a), osilodrostat (b), and CHEMBL162496 (c).

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    Figure 4

    Figure 4. Predicted binding mode of compounds X1 (a) and X21 (b) into the aromatase (CYP19A1) binding site.

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    Figure 5

    Figure 5. Antiproliferative in vitro effects of compound X21 and letrozole on human MCF-7 (Estrogen Receptor+), MDA-MB-231 (Estrogen Receptor−), and HNDF healthy cells at 24 h (A), 48 h (B), and 72 h (C). The data are presented as mean (±SEM) percentage values of vehicle-treated cell proliferation. Pro-apoptotic effects were observed in MCF-7 and MDA-MB-231 cells (D) using the cell death detection ELISA Plus kit. The internal negative control was provided by an ELISA kit. Columns and bars, mean values ± SD, respectively.

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    Figure 6

    Figure 6. Luminex analysis of the Akt/mTOR cell signaling pathway in MCF-7 cells treated with compound X21 for 24 h at the experimental antiproliferative IC50 (700 nM). Results were reported as the percentage of the phosphorylated protein/total protein ratio vs 100% of vehicle-treated cells. C, vehicle-treated control; AKT, protein kinase B; GSK, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homologue; TSC2, tuberous sclerosis complex 2; RP6S, ribosomal protein S6; IGF1R, insulin-like growth factor 1 (IGF-1) receptor; IR, insulin receptor; IRS1, insulin receptor substrate 1; p70S6K, ribosomal protein S6 kinase beta-1. Columns and bars, mean values ± SD, respectively.

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      Chapman, J.-A. W.; Meng, D.; Shepherd, L.; Parulekar, W.; Ingle, J. N.; Muss, H. B.; Palmer, M.; Yu, C.; Goss, P. E. Competing Causes of Death From a Randomized Trial of Extended Adjuvant Endocrine Therapy for Breast Cancer. JNCI J. Natl. Cancer Inst. 2008, 100 (4), 252– 260,  DOI: 10.1093/jnci/djn014
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      Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for breast cancer
      Chapman Judith-Anne W; Meng Daniel; Shepherd Lois; Parulekar Wendy; Ingle James N; Muss Hyman B; Palmer Michael; Yu Changhong; Goss Paul E
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      BACKGROUND: Older women with early-stage breast cancer experience higher rates of non-breast cancer-related death. We examined factors associated with cause-specific death in a large cohort of breast cancer patients treated with extended adjuvant endocrine therapy. METHODS: In the MA.17 trial, conducted by the National Cancer Institute of Canada Clinical Trials Group, 5170 breast cancer patients (median age = 62 years; range = 32-94 years) who were disease free after approximately 5 years of adjuvant tamoxifen treatment were randomly assigned to treatment with letrozole (2583 women) or placebo (2587 women). The median follow-up was 3.9 years (range 0-7 years). We investigated the association of 11 baseline factors with the competing risks of death from breast cancer, other malignancies, and other causes. All statistical tests were two-sided likelihood ratio criterion tests. RESULTS: During follow-up, 256 deaths were reported (102 from breast cancer, 50 from other malignancies, 100 from other causes, and four from an unknown cause). Non-breast cancer deaths accounted for 60% of the 252 known deaths (72% for those > or = 70 years and 48% for those < 70 years). Two baseline factors were differentially associated with type of death: cardiovascular disease was associated with a statistically significant increased risk of death from other causes (P.002), and osteoporosis was associated with a statistically significant increased risk of death from other malignancies (P.05). An increased risk of breast cancer-specific death was associated with lymph node involvement (P < .001). Increased risk of death from all three causes was associated with older age (P < .001). CONCLUSIONS: Non-breast cancer-related deaths were more common than breast cancer-specific deaths in this cohort of 5-year breast cancer survivors, especially among older women.
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      Wang, Yan; Wang, Qi; Zhao, Yingnan; Gong, Dezheng; Wang, Dongmei; Li, Cong; Zhao, Henan
      Circulation Journal (2010), 74 (4), 634-643CODEN: CJIOBY; ISSN:1346-9843. (Japanese Circulation Society)
      Background: Female sex hormones may have protective effects against arrhythmias, including reperfusion arrhythmias (RAs), but the mechanisms are still not completely known. Methods and Results: Serial changes in rat hearts (rhythm, apoptosis and the its influencing factors; cardiac vinculin mRNA expression and connexin43 (Cx43) dephosphorylation) were examd. during periods of ischemia-reperfusion with and without estrogen treatment. After reperfusion, although the incidence of arrhythmias became higher in both the vehicle-group and estrogen-group, compared with the ischemia period, estrogen prevented reperfusion-induced upregulation of the incidence of arrhythmias, esp. ventricular premature beats (VPB) and ventricular tachycardia (VT). The duration of VT and fibrillation, and the no. of VPB and VT, were all significantly decreased in the estrogen-group. The expression of cardiac vinculin mRNA decreased significantly in the vehicle-group but not in the estrogen-group. Cx43 dephosphorylation and myocyte apoptosis increased in both groups, but the values for the estrogen-group were all markedly lower than those for the vehicle-group. A selective estrogen receptor (ER) β agonist prevented reperfusion-induced upregulation of the incidence of both VPB and VT significantly; a selective ERα agonist had no significant influence. Conclusions: Estrogen can protect the heart against RAs, at least in part, mediated through gap junctions. Upregulation of ERβ but not ERα mediated most of the estrogen-induced cardioprotection against RA.
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    12. 12
      Beer, S.; Reincke, M.; Kral, M.; Callies, F.; Strömer, H.; Dienesch, C.; Steinhauer, S.; Ertl, G.; Allolio, B.; Neubauer, S. High-Dose 17β–Estradiol Treatment Prevents Development of Heart Failure Post–Myocardial Infarction in the Rat. Basic Res. Cardiol. 2007, 102 (1), 9– 18,  DOI: 10.1007/s00395-006-0608-1
      12
      High-dose 17β-estradiol treatment prevents development of heart failure post-myocardial infarction in the rat
      Beer, Stephanie; Reincke, Martin; Kral, Maike; Callies, Frank; Stroemer, Hinrik; Dienesch, Charlotte; Steinhauer, Sonja; Ertl, Georg; Allolio, Bruno; Neubauer, Stefan
      Basic Research in Cardiology (2007), 102 (1), 9-18CODEN: BRCAB7; ISSN:0300-8428. (Steinkopff Verlag)
      Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or β-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examd. whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. Female rats were treated with 17β-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to exptl. myocardial infarction. Eight weeks after infarction, in vivo echocardiog. and hemodynamic measurements as well as isolated heart perfusion were performed. In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diams. (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-vol. curves occurring in untreated infarcted hearts was completely prevented by estrogen. High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment. However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.
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    13. 13
      Gardner, J. D.; Murray, D. B.; Voloshenyuk, T. G.; Brower, G. L.; Bradley, J. M.; Janicki, J. S. Estrogen Attenuates Chronic Volume Overload Induced Structural and Functional Remodeling in Male Rat Hearts. Am. J. Physiol.-Heart Circ. Physiol. 2010, 298 (2), H497– H504,  DOI: 10.1152/ajpheart.00336.2009
      There is no corresponding record for this reference.
    14. 14
      Donaldson, C.; Eder, S.; Baker, C.; Aronovitz, M. J.; Weiss, A. D.; Hall-Porter, M.; Wang, F.; Ackerman, A.; Karas, R. H.; Molkentin, J. D.; Patten, R. D. Estrogen Attenuates Left Ventricular and Cardiomyocyte Hypertrophy by an Estrogen Receptor–Dependent Pathway That Increases Calcineurin Degradation. Circ. Res. 2009, 104 (2), 265– 275,  DOI: 10.1161/CIRCRESAHA.108.190397
      14
      Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway That Increases Calcineurin Degradation
      Donaldson, Cameron; Eder, Sarah; Baker, Corey; Aronovitz, Mark J.; Weiss, Alexandra Dabreo; Hall-Porter, Monica; Wang, Feng; Ackerman, Adam; Karas, Richard H.; Molkentin, Jeffery D.; Patten, Richard D.
      Circulation Research (2009), 104 (2), 265-275CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)
      Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a crit. role in the development of pathol. hypertrophy. Previous exptl. studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17β-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 wk, mice underwent physiol. evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were assocd. with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degrdn. that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degrdn., unveiling a novel mechanism by which E2 and ERs regulate pathol. LV and cardiomyocyte growth.
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    15. 15
      Arias-Loza, P.-A.; Muehlfelder, M.; Elmore, S. A.; Maronpot, R.; Hu, K.; Blode, H.; Hegele-Hartung, C.; Fritzemeier, K. H.; Ertl, G.; Pelzer, T. Differential Effects of 17β-Estradiol and of Synthetic Progestins on Aldosterone-Salt–Induced Kidney Disease. Toxicol. Pathol. 2009, 37 (7), 969– 982,  DOI: 10.1177/0192623309350475
      15
      Differential effects of 17β-estradiol and of synthetic progestins on aldosterone-salt-induced kidney disease
      Arias-Loza, Paula-Anahi; Muehlfelder, Melanie; Elmore, Susan A.; Maronpot, Robert; Hu, Kai; Blode, Hartmut; Hegele-Hartung, Christa; Fritzemeier, Karl Heinrich; Ertl, Georg; Pelzer, Theo
      Toxicologic Pathology (2009), 37 (7), 969-982CODEN: TOPADD; ISSN:0192-6233. (Sage Publications)
      Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown. Identify the function of estrogens and of different synthetic progestins on aldosterone salt-mediated renal disease. The role of 17β-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment. Aldo-salt treatment of intact, ovariectomized, and estradiol-treated female rats resulted in remnant kidney hypertrophy without structural damage. Co-treatment with MPA, but not with drospirenone, increased kidney hypertrophy, fluid turnover, sodium retention, and potassium excretion. Medroxyprogesterone acetate also caused glomerular, vascular, tubular, and interstitial lesions that were accompanied by increased blood pressure and enhanced NADPH oxidase (p67phox) and sodium channel (α-ENaC) expression. Drospirenone, a progestin with anti-mineralocorticoid function, and spironolactone prevented kidney hypertrophy, hypertension, and sodium retention. Drospirenone and spironolactone also increased renal angiotensin II type 2 receptor expression and relieved aldosterone-induced suppression of serum angiotensin II levels. The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake.
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    16. 16
      Kwan, M. L.; Yao, S.; Laurent, C. A.; Roh, J. M.; Quesenberry, C. P.; Kushi, L. H.; Lo, J. C. Changes in Bone Mineral Density in Women with Breast Cancer Receiving Aromatase Inhibitor Therapy. Breast Cancer Res. Treat. 2018, 168 (2), 523– 530,  DOI: 10.1007/s10549-017-4626-5
      16
      Changes in bone mineral density in women with breast cancer receiving aromatase inhibitor therapy
      Kwan, Marilyn L.; Yao, Song; Laurent, Cecile A.; Roh, Janise M.; Quesenberry, Charles P., Jr.; Kushi, Lawrence H.; Lo, Joan C.
      Breast Cancer Research and Treatment (2018), 168 (2), 523-530CODEN: BCTRD6; ISSN:0167-6806. (Springer)
      Purpose: We assessed bone mineral d. (BMD) change with aromatase inhibitor (AI) treatment in a contemporary cohort of women with breast cancer treated in Kaiser Permanente Northern California. Methods: Percent and estd. annual percent changes in BMD at the total hip and lumbar spine were examd. in 676 women receiving AI therapy who had two serial BMD reports available (at least 1 yr apart) before and after AI initiation (N = 317) or during continued AI therapy (N = 359). BMD changes were examd. at the total hip and lumbar spine and compared by age and clin. subgroups. Results: Women experienced BMD declines after AI initiation or continued therapy, with median annual percent change - 1.2% (interquartile range, IQR - 2.4 to - 0.1%) at the hip and - 1.0% (IQR - 2.3 to 0.1%) at the spine after AI initiation, and - 1.1% (IQR - 2.4 to 0.1%) at the hip and - 0.9% (IQR - 2.4 to 0.5%) at the spine during continued therapy. Higher levels of bone loss were obsd. among younger (< 55 years) compared with older (≥ 75 years) women at the hip (- 1.6% vs. - 0.8%) and at the spine (- 1.5% vs. - 0.5%) after AI initiation, and at the hip (- 1.4% vs. - 1.2%) and at the spine (- 2.4% vs. - 0.001%) during continued therapy. Conclusions: Small but consistent declines in total hip and lumbar spine BMD were present in breast cancer patients following AI therapy initiation or continued AI therapy. Although the overall rates of osteoporosis were low, greater estd. levels of annual bone loss were evident among women < 55 years.
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    17. 17
      Tian, W.; Wu, M.; Deng, Y. Comparison of Changes in the Lipid Profiles of Eastern Chinese Postmenopausal Women With Early-Stage Breast Cancer Treated With Different Aromatase Inhibitors: A Retrospective Study. Clin. Pharmacol. Drug Dev. 2018, 7 (8), 837– 843,  DOI: 10.1002/cpdd.420
      17
      Comparison of Changes in the Lipid Profiles of Eastern Chinese Postmenopausal Women With Early-Stage Breast Cancer Treated With Different Aromatase Inhibitors: A Retrospective Study
      Tian, Wei; Wu, Miaowei; Deng, Yongchuan
      Clinical Pharmacology in Drug Development (2018), 7 (8), 837-843CODEN: CPDDAH; ISSN:2160-7648. (John Wiley & Sons, Inc.)
      Cardiovascular morbidity is closely assocd. with serum lipid level. We aimed to investigate the effects of different aromatase inhibitors, including letrozole, anastrozole, and exemestane, on the lipid profile of eastern Chinese breast cancer patients. We evaluated a retrospective cohort of eastern Chinese postmenopausal women with early-stage breast cancer who received aromatase inhibitors. A total of 116 postmenopausal women with early-stage breast cancer without prior cardiovascular disease were included. Lipid changes at 3, 6, 12, and 24 mo were compared across the endocrine therapy categories. Our data demonstrated that exemestane treatment significantly decreased triglyceride level compared with letrozole after 24 mo. However, the aromatase inhibitors had almost equiv. impacts on high-d. liportein cholesterol, low-d. lipoprotein cholesterol, and triglyceride after long-term aromatase inhibitor treatment. As a small-size retrospective study, our data do not support a judgment about whether one AI or another carries more or less risk in terms of lipid disorders in eastern Chinese breast cancer patients. The exact effects need further randomized, controlled trials to investigate.
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    18. 18
      Castelli, W. P. Cardiovascular Disease in Women. Am. J. Obstet. Gynecol. 1988, 158 (6), 1553– 1560,  DOI: 10.1016/0002-9378(88)90189-5
      18
      Cardiovascular disease in women
      Castelli W P
      American journal of obstetrics and gynecology (1988), 158 (6 Pt 2), 1553-60, 1566-7 ISSN:0002-9378.
      Cardiovascular disease is the leading cause of death in American women. Atherosclerotic diseases, primarily myocardial infarction and stroke, are important causes of morbidity and mortality among women. Contrary to popular belief, the actual number of myocardial infarctions in men and women is similar, although women develop cardiovascular disease an average of 10 years later than do men. Total serum cholesterol level is a major indicator of risk of coronary heart disease; for every 1% increase in the total serum cholesterol level, a 2% increase in incidence of coronary heart disease is found. A high level of low-density lipoproteins is an independent risk factor for coronary heart disease in both mean and women, but high triglyceride level is an independent risk factor only in women. Conversely, the higher the level of high-density lipoprotein, the lower the risk of coronary heart disease. To reduce the risk of coronary heart disease, target levels of total serum cholesterol must be lowered from 300 to 200 mg/dl. If the total cholesterol/high-density lipoprotein ratio is greater than or equal to 4.5 of if the low-density lipoprotein concentration is greater than 150 mg/dl, the patient is at high risk for coronary heart disease. Clinical trials that use diet or drugs to lower serum cholesterol levels have consistently shown a 2% reduction in the incidence of coronary heart disease for every 1% reduction in total serum cholesterol level.
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    19. 19
      Fischer, M. Renin Angiotensin System and Gender Differences in the Cardiovascular System. Cardiovasc. Res. 2002, 53 (3), 672– 677,  DOI: 10.1016/S0008-6363(01)00479-5
      19
      Renin angiotensin system and gender differences in the cardiovascular system
      Fischer, Marcus; Baessler, Andrea; Schunkert, Heribert
      Cardiovascular Research (2002), 53 (3), 672-677CODEN: CVREAU; ISSN:0008-6363. (Elsevier Science B.V.)
      A review. To explain gender-related differences of the cardiovascular system, the renin-angiotensin system experienced intensive exploration. Indeed, the development of hypertension as well as the progression of coronary artery disease and heart failure have 2 factors in common: (1) display distinct gender specific characteristics and (2) are enhanced by the renin-angiotensin system. It is therefore interesting to note that data from exptl. animals, epidemiol. surveys, and clin. investigations suggest that the components of the circulating as well as tissue-based renin-angiotensin system are markedly affected by gender. However, the issue is complicated by counter-regulatory effects of estrogen on the system with the substrate, on one hand, and the processing enzymes as well as the chief receptor, on the other hand. In fact, angiotensinogen is up-regulated particularly by oral administration of estrogen, whereas renin, angiotensin-converting enzyme (ACE), and AT-1 receptor are down-regulated by the hormone. While under well-defined exptl. conditions the net effect of estrogen appears to result in suppression of the renin-angiotensin system, the clin. situation may be more complex. The judgment is further complicated by the difficulty in precisely measuring the activity of the system at the tissue level. Moreover, clin. relevant read-outs for the activity of the renin-angiotensin system may be regulated multifactorially or only indirectly affected by the system. Nevertheless, the undisputable, profound biochem. changes in the renin-angiotensin system related to the estrogen status allow speculation that such interaction explains some of the differences in the cardiovascular system of men and women.
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    20. 20
      Roesch, D. M.; Tian, Y.; Zheng, W.; Shi, M.; Verbalis, J. G.; Sandberg, K. Estradiol Attenuates Angiotensin-Induced Aldosterone Secretion in Ovariectomized Rats. Endocrinology 2000, 141 (12), 4629– 4636,  DOI: 10.1210/endo.141.12.7822
      20
      Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats
      Roesch, Darren M.; Tian, Ying; Zheng, Wei; Shi, Min; Verbalis, Joseph G.; Sandberg, Kathryn
      Endocrinology (2000), 141 (12), 4629-4636CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)
      Estrogen replacement therapy significantly reduces the risk of cardiovascular disease in postmenopausal women. Previous studies indicate that estradiol (E2) decreases angiotensin II (AT) receptor d. in the adrenal and pituitary in NaCl-loaded rats. We used an in vivo model that eliminates the potentially confounding influence of ACTH to det. whether the E2-induced decrease in adrenal AT receptor expression affects aldosterone responses to angiotensin II (Ang II). Female rats were ovariectomized, treated with oil (OVX) or E2(OVX+E2; 10 μg, s.c.) for 14 days, and fed a NaCl-deficient diet for the last 7 days to maximize adrenal AT receptor expression and responsiveness. On days 12-14 rats were treated with dexamethasone (DEX; 25 μg, i.p., every 12 h) to suppress plasma ACTH. On day 14 aldosterone secretion was measured after a 30-min infusion of Ang II (330 ng/min). Ang II infusion increased the peak plasma aldosterone levels to a lesser degree in the OVX+E2 than in the OVX rats (OVX, 1870 pg/mL; OVX+E2, 1010 pg/mL). Ang II-induced ACTH and aldosterone secretion was also studied in rats that were not treated with DEX. In the absence of DEX, the peak plasma aldosterone response was also significantly decreased (OVX, 5360 pg/mL; OVX+E2, 2960 pg/mL). However, E2 also reduced the plasma ACTH response to Ang II (OVX, 220 pg/mL; OVX+E2, 160 pg/mL), suggesting that reduced pituitary ACTH responsiveness to Ang II contributes to the effect of E2 on Ang II-induced aldosterone secretion. Adrenal AT1 binding studies confirmed that E2 significantly reduces adrenal AT1 receptor expression in both the presence and absence of DEX in NaCl-deprived rats. These results indicate that E2-induced decreases in pituitary and adrenal AT1 receptor expression are assocd. with attenuated pituitary ACTH and adrenal aldosterone responses to Ang II and suggest that estrogen replacement therapy may modulate Ang II-stimulated aldosterone secretion as part of its well known cardioprotective actions.
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    21. 21
      Chappell, M. C.; Gallagher, P. E.; Averill, D. B.; Ferrario, C. M.; Brosnihan, K. B. Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat. Hypertension 2003, 42 (4), 781– 786,  DOI: 10.1161/01.HYP.0000085210.66399.A3
      21
      Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2.Lewis rat
      Chappell, Mark C.; Gallagher, Patricia E.; Averill, David B.; Ferrario, Carlos M.; Brosnihan, K. Bridget
      Hypertension (2003), 42 (4, Pt. 2), 781-786CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
      The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 wk resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 wk, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195±3.7 mm Hg vs. 141±4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concn., as well as urinary excretion of Ang II, 8-isoprostane F2α, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 wk (125±2.9 mm Hg, n=7, P<0.01 vs. OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113±5.4 mm Hg (n=6, P<0.01 vs. OVX and sham). The attenuation of the hypertension was still evident 7 wk after complete withdrawal of treatment (124±4.1 mm Hg at week 23). In summary, the OVX mRen.2.Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2.Lewis strain, possibly by limiting activation of the renin-angiotensin system.
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    22. 22
      Harrison-Bernard, L. M.; Schulman, I. H.; Raij, L. Postovariectomy Hypertension Is Linked to Increased Renal AT1 Receptor and Salt Sensitivity. Hypertension 2003, 42 (6), 1157– 1163,  DOI: 10.1161/01.HYP.0000102180.13341.50
      22
      Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity
      Harrison-Bernard, Lisa M.; Schulman, Ivonne Hernandez; Raij, Leopoldo
      Hypertension (2003), 42 (6), 1157-1163CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
      The functional balance between angiotensin II (Ang II) and nitric oxide (NO) plays a key role in modulating salt sensitivity. Estrogen has been shown to downregulate angiotensin type 1 (AT1) receptor expression and to increase the bioavailability of endothelium-derived NO, which decreases AT1 receptor expression. The present study tests the hypothesis that in the presence of genetic salt sensitivity, deficiency of endogenous estrogens after ovariectomy (OVX) fosters an upregulation of Ang II. Female Dahl salt-resistant (DR), Dahl salt-sensitive (DS), Wistar-Kyoto (WKY), and spontaneously hypertensive (SHR) rats underwent bilateral OVX or sham surgery (SHX) and were fed a normal salt diet (0.5% NaCl) for 14 wk. Systolic blood pressures were measured every 2 wk and were not significantly different between OVX and SHX for DR, WKY, and SHR groups. However, at the end of 14 wk of normal salt diet, hypertension developed in DS OVX but not SHX rats (160±3 vs. 136±3 mm Hg; P<0.05). Hypertension also developed in DS OVX rats pair-fed a normal salt diet (166±7 mm Hg). Development of hypertension in DS OVX rats was prevented by estrogen replacement (132±3 mm Hg), AT1 receptor blockade (119±3 mm Hg), or feeding a very low salt diet (0.1% NaCl; 129±4 mm Hg). Renal AT1 receptor protein expression was significantly elevated 2-fold in DS OVX relative to SHX rats and was prevented by estrogen replacement. These data strongly suggest that after OVX in salt-sensitive rats there is a lower threshold for the hypertensinogenic effect of salt that is linked to an activation of Ang II.
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    23. 23
      Krishnamurthi, K.; Verbalis, J. G.; Zheng, W.; Wu, Z.; Clerch, L. B.; Sandberg, K. Estrogen Regulates Angiotensin AT1 Receptor Expression via Cytosolic Proteins That Bind to the 52 Leader Sequence of the Receptor mRNA. Endocrinology 1999, 140 (11), 5435– 5438,  DOI: 10.1210/endo.140.11.7242
      23
      Estrogen regulates angiotensin AT1 receptor expression via cytosolic proteins that bind to the 5' leader sequence of the receptor mRNA
      Krishnamurthi, Kamakshi; Verbalis, Joseph G.; Zheng, Wei; Wu, Zheng; Clerch, Linda B.; Sandberg, Kathryn
      Endocrinology (1999), 140 (11), 5435-5438CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)
      Two of the most highly recognized factors implicated in the pathogenesis of hypertension, atherosclerosis, congestive heart failure and assocd. cardiovascular disease are the renin-angiotensin system (RAS) and estrogen. A major effect of estrogen results from its influence on the RAS. β-Estradiol (E2) replacement in ovariectomized (OVX) rats significantly decreased type 1 angiotensin (AT1) receptor expression in the pituitary and adrenal, whereas it significantly increased receptor expression in the uterus when compared to OVX controls. Addnl. evidence demonstrated an important influence of estrogen on a recently discovered post-transcriptional mechanism for regulating expression of the AT1 receptor. This mechanism consists of cytosolic RNA binding proteins (BPs) that recognize the 5' leader sequence (5'LS) of the receptor mRNA. The activities of these 5'LS BPs were modulated by estrogen in an inverse manner to AT1 receptor regulation. Moreover, in vitro translation assays in wheat germ lysates suggested that the 5'LS BPs inhibited AT1 receptor translation. Our data therefore indicate that hormonal regulation of AT1 receptors involves modulation of 5'LS BPs by estrogen. These findings may in part account for the obsd. protective effects of estrogen on cardiovascular disease.
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    24. 24
      Ries, C.; Lucas, S.; Heim, R.; Birk, B.; Hartmann, R. W. Selective Aldosterone Synthase Inhibitors Reduce Aldosterone Formation in Vitro and in Vivo. J. Steroid Biochem. Mol. Biol. 2009, 116 (3–5), 121– 126,  DOI: 10.1016/j.jsbmb.2009.04.013
      24
      Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo
      Ries, Christina; Lucas, Simon; Heim, Ralf; Birk, Barbara; Hartmann, Rolf W.
      Journal of Steroid Biochemistry and Molecular Biology (2009), 116 (3-5), 121-126CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
      Aldosterone plays a crucial role in salt and water homeostasis but in case of pathol. increased plasma aldosterone levels it is also involved in the development and the progression of severe cardiovascular diseases like heart failure and myocardial fibrosis. For the treatment of these diseases we propose inhibition of the aldosterone forming enzyme CYP11B2 as a new pharmacol. strategy. We recently developed in vitro highly potent and selective inhibitors of human CYP11B2, but the evidence of their in vivo activity is still missing. For this purpose, rat aldosterone synthase gene was cloned and expressed in V79MZ cells to establish a new screening assay for the identification of "rat-active" substances. Compds. from the class of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones showed a moderate inhibitory effect (65% at 2 μM) on rat CYP11B2 in vitro. Furthermore, it diminished the conversion of deoxycorticosterone to aldosterone in rat adrenals and significantly reduced plasma aldosterone levels in vivo.
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    25. 25
      Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem. 2014, 57 (19), 7874– 7887,  DOI: 10.1021/jm5006463
      25
      Polypharmacology: Challenges and Opportunities in Drug Discovery
      Anighoro, Andrew; Bajorath, Jurgen; Rastelli, Giulio
      Journal of Medicinal Chemistry (2014), 57 (19), 7874-7887CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biol. target, shares the spotlight with an emerging and alternative polypharmacol. approach. Polypharmacol. suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this review, we will compare advantages and disadvantages of multitarget vs. combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multitarget drugs.
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    26. 26
      Pinzi, L.; Tinivella, A.; Gagliardelli, L.; Beneventano, D.; Rastelli, G. LigAdvisor: A Versatile and User-Friendly Web-Platform for Drug Design. Nucleic Acids Res. 2021, 49 (W1), W326– W335,  DOI: 10.1093/nar/gkab385
      26
      LigAdvisor: a versatile and user-friendly web-platform for drug design
      Pinzi, Luca; Tinivella, Annachiara; Gagliardelli, Luca; Beneventano, Domenico; Rastelli, Giulio
      Nucleic Acids Research (2021), 49 (W1), W326-W335CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      Although several tools facilitating in silico drug design are available, their results are usually difficult to integrate with publicly available information or require further processing to be fully exploited. The rational design of multi-target ligands (polypharmacol.) and the repositioning of known drugs towards unmet therapeutic needs (drug repurposing) have raised increasing attention in drug discovery, although they usually require careful planning of tailored drug design strategies. Computational tools and data-driven approaches can help to reveal novel valuable opportunities in these contexts, as they enable to efficiently mine publicly available chem., biol., clin., and disease-related data. Based on these premises, we developed LigAdvisor, a data-driven webserver which integrates information reported in DrugBank, Protein Data Bank, UniProt, Clin. Trials and Therapeutic Target Database into an intuitive platform, to facilitate drug discovery tasks as drug repurposing, polypharmacol., target fishing and profiling. As designed, LigAdvisor enables easy integration of similarity estn. results with clin. data, thereby allowing a more efficient exploitation of information in different drug discovery contexts. Users can also develop customizable drug design tasks on their own mols., by means of ligand- and target-based search modes, and download their results.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFWgtbrO&md5=eee342dee01ed98315cd33d2f25a288d
    27. 27
      Ankley, G. T.; Kahl, M. D.; Jensen, K. M.; Hornung, M. W.; Korte, J. J.; Makynen, E. A.; Leino, R. L. Evaluation of the Aromatase Inhibitor Fadrozole in a Short-Term Reproduction Assay with the Fathead Minnow (Pimephales Promelas). Toxicol. Sci. 2002, 67 (1), 121– 130,  DOI: 10.1093/toxsci/67.1.121
      27
      Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas)
      Ankley, Gerald T.; Kahl, Michael D.; Jensen, Kathleen M.; Hornung, Michael W.; Korte, Joseph J.; Makynen, Elizabeth A.; Leino, Richard L.
      Toxicological Sciences (2002), 67 (1), 121-130CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)
      Cytochrome P 450 aromatase (CYP19) is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such as β-estradiol (E2). The objective of this study was to assess effects of the CYP19 inhibitor fadrozole on fathead minnow (Pimephales promelas) reproductive endocrinol. and physiol. in a short-term reprodn. assay proposed for identifying specific classes of endocrine-disrupting chems. A concn.-dependent redn. in fecundity was obsd. in fish exposed for 21 days to water concns. of fadrozole ranging from 2 to 50 μg/l. Consistent with the expected mechanism of action, there was a significant inhibition of brain aromatase activity in both male and female fathead minnows exposed to fadrozole. In females, this inhibition was accompanied by a concn.-dependent decrease in plasma E2 and vitellogenin concns.; the latter observation is consistent with the fact that activation of the estrogen receptor by E2 initiates hepatic vitellogenin prodn. in oviparous vertebrates. Histol. assessment of ovaries from females exposed to fadrozole indicated a decrease in mature oocytes and an increase in preovulatory atretic follicles. Exposure of male fathead minnows to fadrozole significantly increased plasma concns. of the androgens testosterone (T) and 11-ketotestosterone (KT) and resulted in a marked accumulation of sperm in the tests. Results of this study indicate that the proposed fathead minnow assay should effectively identify test chems. as potential aromatase inhibitors, both in the context of their reproductive toxicity and the specific mechanism of action. These results also should be of utility in assessing the potential ecol. risk of CYP19 inhibitors, in particular in the context of relating alterations in subcellular indicators of endocrine function (changes in steroids, proteins) to adverse consequences in the whole organism.
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    28. 28
      Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager, A. Fadrozole Hydrochloride: A Potent, Selective, Nonsteroidal Inhibitor of Aromatase for the Treatment of Estrogen-Dependent Disease. J. Med. Chem. 1991, 34 (2), 725– 736,  DOI: 10.1021/jm00106a038
      28
      Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease
      Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager, A.
      Journal of Medicinal Chemistry (1991), 34 (2), 725-36CODEN: JMCMAR; ISSN:0022-2623.
      The prepn. of 5-phenyl-5,6,7,8-tetrahydroimidazopyridine derivs. I (R = cyano, Br, CH2OH, Me, CO2H, CO2Et) and their evaluation as inhibitors for aromatase and estrogen prodn. was described; the most potent aromatase inhibitor was (+)-I (R = cyano), i.e. fadrozole (CGS 16949A). The mol. structure-activity relationship was discussed.
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    29. 29
      Ménard, J.; Pascoe, L. Can the Dextroenantiomer of the Aromatase Inhibitor Fadrozole Be Useful for Clinical Investigation of Aldosterone-Synthase Inhibition?. J. Hypertens. 2006, 24 (6), 993– 997,  DOI: 10.1097/01.hjh.0000226183.98439.b3
      29
      Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?
      Menard, Joel; Pascoe, Leigh
      Journal of Hypertension (2006), 24 (6), 993-997CODEN: JOHYD3; ISSN:0263-6352. (Lippincott Williams & Wilkins)
      A review. The beneficial effects of spironolactone, eplerenone, amiloride, and potassium in preventing cardiovascular damage in various exptl. models of salt-induced hypertension can be dissocd. from blood pressure effects, and have drawn attention to the direct genomic and non-genomic actions of aldosterone at the level of the vessels, the heart, and the kidneys. Exposure to endogenous aldosterone could be decreased by direct and specific aldosterone-synthase inhibition. FAD 286A, the dextroenantiomer of the aromatase inhibitor fadrozole, might be a 1st candidate to investigate in humans, the physiol. impact and therapeutic properties of aldosterone-synthase inhibition, esp. in various forms of primary aldosteronism.
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    30. 30
      Smith, I. E.; Norton, A. Fadrozole and Letrozole in Advanced Breast Cancer: Clinical and Biochemical Effects. Breast Cancer Res. Treat. 1998, 49 (S1), S67– S71,  DOI: 10.1023/A:1006005024377
      30
      Fadrozole and letrozole in advanced breast cancer: clinical and biochemical effects
      Smith, Ian E.; Norton, Alison
      Breast Cancer Research and Treatment (1998), 49 (Suppl. 1), S67-S71CODEN: BCTRD6; ISSN:0167-6806. (Kluwer Academic Publishers)
      A review with 18 refs.
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    31. 31
      Lamberts, S. W. J.; Bruining, H. A.; Marzouk, H.; Zuiderwijk, J.; Uitterlinden, P.; Blijd, J. J.; Hackeng, W. H. L.; Jong, F. H. D. The New Aromatase Inhibitor CGS-16949A SuppressesAldosterone and Cortisol Production by Human Adrenal Cells in Vitro. J. Clin. Endocrinol. Metab. 1989, 69 (4), 896– 901,  DOI: 10.1210/jcem-69-4-896
      31
      The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro
      Lamberts, S. W. J.; Bruining, H. A.; Marzouk, H.; Zuiderwijk, J.; Uitterlinden, P.; Blijd, J. J.; Hackeng, W. H. L.; De Jong, F. H.
      Journal of Clinical Endocrinology and Metabolism (1989), 69 (4), 896-901CODEN: JCEMAZ; ISSN:0021-972X.
      CGS-16949A is a new orally active nonsteroidal aromatase inhibitor which is more than 100-fold more potent than aminoglutethimide. This compd. is an imidazole deriv., and therefore, its possible effect on cytochrome P 450-dependent enzyme activities in the adrenal gland was evaluated. In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10-7-10-6M is a potent 11β-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concn. of metyrapone (IC50 for both compds., 10-7-5 × 10-7M). Etomidate was a more potent 11 β-hydroxylase inhibitor (IC50, ∼10-8M), while 10-7-10-6M ketoconazole caused (via 17α-hydroxylase inhibition) a similar inhibition of cortisol release as 10-7M CGS-16949A (IC50, 10-7-5 × 10-5M). The 11β-hydroxylase inhibition by CGS-16949A was accompanied by a dose-dependent increase in the release of precursor steroids by the adrenocortical cells in vitro, including deoxycortisol, 17-hydroxyprogesterone, and androstenedione. Aldosterone release was suppressed 50% by 10-8M CGS-16949A, while the IC50 for cortisol in the same cells was 10-7M. Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also suppressed by CGS-16949A. It is concluded that the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11β-hydroxylase which is equipotent to metyrapone. At present it is unclear whether the compd. at the dose that causes complete aromatase inhibition in vivo also affects stress-induced cortisol release in man. Also, CGS-16949A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10-9M) and on a tumorous aldosterone secretion. CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.
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    32. 32
      Hu, Q.; Yin, L.; Hartmann, R. W. Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases: Miniperspective. J. Med. Chem. 2014, 57 (12), 5011– 5022,  DOI: 10.1021/jm401430e
      32
      Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases
      Hu, Qingzhong; Yin, Lina; Hartmann, Rolf W.
      Journal of Medicinal Chemistry (2014), 57 (12), 5011-5022CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and vol., recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathol. circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clin. trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.
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    33. 33
      Roumen, L.; Peeters, J. W.; Emmen, J. M. A.; Beugels, I. P. E.; Custers, E. M. G.; De Gooyer, M.; Plate, R.; Pieterse, K.; Hilbers, P. A. J.; Smits, J. F. M.; Vekemans, J. A. J.; Leysen, D.; Ottenheijm, H. C. J.; Janssen, H. M.; Hermans, J. J. R. Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-Imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2). J. Med. Chem. 2010, 53 (4), 1712– 1725,  DOI: 10.1021/jm901356d
      33
      Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
      Roumen, Luc; Peeters, Joris W.; Emmen, Judith M. A.; Beugels, Ilona P. E.; Custers, Erica M. G.; de Gooyer, Marcel; Plate, Ralf; Pieterse, Koen; Hilbers, Peter A. J.; Smits, Jos F. M.; Vekemans, Jef A. J.; Leysen, Dirk; Ottenheijm, Harry C. J.; Janssen, Henk M.; Hermans, J. J. Rob
      Journal of Medicinal Chemistry (2010), 53 (4), 1712-1725CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, three-dimensional modeling of CYP11B2 was used to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole (I) as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with the novel lead MOERAS115 (II) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (vs. CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC50 for CYP11B2 6.0 nM, selectivity 19.8). Mol. docking of the inhibitors in the models enabled the generation of posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.
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    34. 34
      Weldon, S. M.; Cerny, M. A.; Gueneva-Boucheva, K.; Cogan, D.; Guo, X.; Moss, N.; Parmentier, J.-H.; Richman, J. R.; Reinhart, G. A.; Brown, N. F. Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2016, 359 (1), 142– 150,  DOI: 10.1124/jpet.116.236463
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      Selectivity of BI 689648, a novel, highly selective aldosterone synthase inhibitor: comparison with FAD286 and LCI699 in nonhuman primates
      Weldon, Steven M.; Cerny, Matthew A.; Gueneva-Boucheva, Kristina; Cogan, Derek; Guo, Xin; Moss, Neil; Parmentier, Jean-Hugues; Richman, Jeremy R.; Reinhart, Glenn A.; Brown, Nicholas F.
      Journal of Pharmacology and Experimental Therapeutics (2016), 359 (1), 142-150CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
      The mineralocorticoid aldosterone is an important regulator of blood pressure, vol., and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis assocd. with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the prodn. of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathol. effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared with human (63%). Using cynomolgus (cyno) monkey-based models, we identified BI 689648 [6-(5-methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide], a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nMagainst AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 [4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile] (3 nM AS; 90 nM CS; 40-fold) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile) (10 nM AS; 80 nM CS; 8-fold). After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concn. of ∼500 nM. For in vivo profiling we used an ACTH-challenge model in which BI 689648 was.20-fold more selective compared with FAD286 and LCI699. Because both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective mols. to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward toward developing ASIs with greater potential for clin. success in cardiometabolic diseases.
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    35. 35
      Matore, B. W.; Banjare, P.; Singh, J.; Roy, P. P. In Silico Selectivity Modeling of Pyridine and Pyrimidine Based CYP11B1 and CYP11B2 Inhibitors: A Case Study. J. Mol. Graph. Model. 2022, 116, 108238  DOI: 10.1016/j.jmgm.2022.108238
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      In silico selectivity modeling of pyridine and pyrimidine based CYP11B1 and CYP11B2 inhibitors: A case study
      Matore, Balaji Wamanrao; Banjare, Purusottam; Singh, Jagadish; Roy, Partha Pratim
      Journal of Molecular Graphics & Modelling (2022), 116 (), 108238CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
      Design of selective drug candidates for highly structural similar targets is a challenging task for researchers. The main objective of this study was to explore the selectivity modeling of pyridine and pyrimidine scaffold towards the highly homologous targets CYP11B1 and CYP11B2 enzymes by in silico (Mol. docking and QSAR) approaches. In this regard, a big dataset (n = 228) of CYP11B1 and CYP11B2 inhibitors were gathered and classified based on heterocyclic ring and the exhaustive anal. was carried out for pyridine and pyrimidinescaffolds. The LibDock algorithm was used to explore the binding pattern, screening, and identify the structural feature responsible for the selectivity of the ligands towards the studied targets. Finally, QSAR anal. was done to explore the correlation between various binding parameters and structural features responsible for the inhibitory activity and selectivity of the ligands in a quant. way. The docking and QSAR anal. clearly revealed and distinguished the importance of structural features, functional groups attached for CYP11B2 and CYP11B1 selectivity for pyridine and pyrimidine analogs. Addnl., the docking anal. highlighted the differentiating amino acids residues for selectivity for ligands for each of the enzymes. The results obtained from this research work will be helpful in designing the selective CYP11B1/CYP11B2 inhibitors.
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    36. 36
      Baumann, M.; Baxendale, I. R. Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multicomponent Reactions. Org. Lett. 2014, 16 (23), 6076– 6079,  DOI: 10.1021/ol502845h
      36
      Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multi-component Reactions
      Baumann, Marcus; Baxendale, Ian R.
      Organic Letters (2014), 16 (23), 6076-6079CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The synthesis of diversely functionalized thioimidazoles through a modern variant of the Marckwald reaction is presented. This new protocol utilizes unprotected carbohydrates as well as simple amine salts as sustainable and biorenewable starting materials. Importantly it was discovered that a bifurcated reaction pathway results from using aldoses and ketoses resp., yielding distinct reaction products in a highly selective manner.
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    37. 37
      Baumann, M.; Baxendale, I. R. A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives: A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives. Eur. J. Org. Chem. 2017, 2017 (44), 6518– 6524,  DOI: 10.1002/ejoc.201700833
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      A Continuous-Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of Etomidate Derivatives
      Baumann, Marcus; Baxendale, Ian R.
      European Journal of Organic Chemistry (2017), 2017 (44), 6518-6524CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented, which generates the corresponding imidazole derivs. I (R = C6H5, 4-BrC6H4, 2,6-F2C6H3,etc.) in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of the thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide byproducts as obsd. in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters II (R = C6H5, 4-BrC6H4, 2,6-F2C6H3, etc.; R1 = Me, Et, i-Pr, CH2CF3) representing new derivs. of the known analgesic etomidate through an efficient one-pot Corey-Gilman-Ganem oxidn. procedure.
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    38. 38
      Baumann, M.; Baxendale, I. R. A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles. Bioorg. Med. Chem. 2017, 25 (23), 6218– 6223,  DOI: 10.1016/j.bmc.2017.01.022
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      A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles
      Baumann, Marcus; Baxendale, Ian R.
      Bioorganic & Medicinal Chemistry (2017), 25 (23), 6218-6223CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethanesulfenyl chloride reagent including its in-line quenching in order to eliminate malodorous and corrosive byproducts. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole was safely prepd. allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.
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    39. 39
      Maligres, P. E.; Waters, M. S.; Weissman, S. A.; McWilliams, J. C.; Lewis, S.; Cowen, J.; Reamer, R. A.; Volante, R. P.; Reider, P. J.; Askin, D. Preparation of a Clinically Investigated Ras Farnesyl Transferase Inhibitor. J. Heterocycl. Chem. 2003, 40 (2), 229– 241,  DOI: 10.1002/jhet.5570400206
      39
      Preparation of a clinically investigated ras farnesyl transferase inhibitor
      Maligres, Peter E.; Waters, Marjorie S.; Weissman, Steven A.; McWilliams, J. Christopher; Lewis, Stephanie; Cowen, Jennifer; Reamer, Robert A.; Volante, R. P.; Reider, Paul J.; Askin, David
      Journal of Heterocyclic Chemistry (2003), 40 (2), 229-241CODEN: JHTCAD; ISSN:0022-152X. (HeteroCorporation)
      The synthesis of ras farnesyl-protein transferase inhibitor I is described on a multi-kilogram scale. Retrosynthetic anal. reveals chloromethylimidazole II and a piperazinone III as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure was developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodol. was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prep. the arylpiperazinone fragment III.
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    40. 40
      Ashburn, T. T.; Thor, K. B. Drug Repositioning: Identifying and Developing New Uses for Existing Drugs. Nat. Rev. Drug Discovery 2004, 3 (8), 673– 683,  DOI: 10.1038/nrd1468
      40
      Drug repositioning: identifying and developing new uses for existing drugs
      Ashburn, Ted T.; Thor, Karl B.
      Nature Reviews Drug Discovery (2004), 3 (8), 673-683CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of prodn. to biotechnol. companies. More and more companies are scanning the existing pharmacopeia for repositioning candidates, and the no. of repositioning success stories is increasing.
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    41. 41
      March-Vila, E.; Pinzi, L.; Sturm, N.; Tinivella, A.; Engkvist, O.; Chen, H.; Rastelli, G. On the Integration of In Silico Drug Design Methods for Drug Repurposing. Front. Pharmacol. 2017, 8, 298,  DOI: 10.3389/fphar.2017.00298
      41
      On the integration of in silico drug design methods for drug repurposing
      March-Vila, Eric; Pinzi, Luca; Sturm, Noe; Tinivella, Annachiara; Engkvist, Ola; Chen, Hongming; Rastelli, Giulio
      Frontiers in Pharmacology (2017), 8 (), 298/1-298/7CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A no. of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease assocns.
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    42. 42
      Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074– D1082,  DOI: 10.1093/nar/gkx1037
      42
      DrugBank 5.0: a major update to the DrugBank database for 2018
      Wishart, David S.; Feunang, Yannick D.; Guo, An C.; Lo, Elvis J.; Marcu, Ana; Grant, Jason R.; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael
      Nucleic Acids Research (2018), 46 (D1), D1074-D1082CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      DrugBank is a web-enabled database contg. comprehensivemol. information about drugs, their mechanisms, their interactions and their targets. First described in 2006, Drug- Bank has continued to evolve over the past 12 years in response to marked improvements to web stds. and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total no. of investigational drugs in the database has grown by almost 300%, the no. of drug-drug interactions has grown by nearly 600% and the no. of SNP-assocd. drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoproteomics). New data have also been added on the status of hundreds of newdrug clin. trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacol. research, pharmaceutical science and drug education.
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    43. 43
      Berman, H. M. The Protein Data Bank. Nucleic Acids Res. 2000, 28 (1), 235– 242,  DOI: 10.1093/nar/28.1.235
      43
      The Protein Data Bank
      Berman, Helen M.; Westbrook, John; Feng, Zukang; Gilliland, Gary; Bhat, T. N.; Weissig, Helge; Shindyalov, Ilya N.; Bourne, Philip E.
      Nucleic Acids Research (2000), 28 (1), 235-242CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The Protein Data Bank (PDB; http://www.rcsb.org/pdb/)is the single worldwide archive of structural data of biol. macromols. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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    44. 44
      Buzdar, A. U.; Robertson, J. F. R.; Eiermann, W.; Nabholtz, J.-M. An Overview of the Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors Anastrozole, Letrozole, and Exemestane. Cancer 2002, 95 (9), 2006– 2016,  DOI: 10.1002/cncr.10908
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      An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane
      Buzdar, Aman U.; Robertson, John F. R.; Eiermann, Wolfgang; Nabholtz, Jean-Marc
      Cancer (New York, NY, United States) (2002), 95 (9), 2006-2016CODEN: CANCAR; ISSN:0008-543X. (John Wiley & Sons, Inc.)
      A review. The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clin. benefit. Because these agents ultimately may be administered for periods of up to 5 yr in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacol. profiles. In the absence of data from direct clin. comparisons, the published literature was reviewed for the clin. pharmacol., pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. At clin. administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 h, 2-4 days, and 27 h, resp. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. All three AIs demonstrated clin. efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clin. significance of these differences remains to be elucidated.
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    45. 45
      Grimm, S. W.; Dyroff, M. C. Inhibition of Human Drug Metabolizing Cytochromes P450 by Anastrozole, a Potent and Selective Inhibitor of Aromatase. Drug Metab. Dispos. Biol. Fate Chem. 1997, 25 (5), 598– 602
      45
      Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase
      Grimm S W; Dyroff M C
      Drug metabolism and disposition: the biological fate of chemicals (1997), 25 (5), 598-602 ISSN:0090-9556.
      Anastrozole (2,2'[5(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]- bis(2-methylproprionitrile)) is a potent third-generation inhibitor of aromatase, currently marketed as a treatment for postmenopausal women with advanced breast cancer. While its potency and selectivity for inhibition of estrogen synthesis has been established in both preclinical and clinical studies, this study used in vitro methods to examine the effects of anastrozole on several drug metabolizing CYP enzymes found in human liver. Human liver microsomes were co-incubated with anastrozole and probe substrates for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6 (dextromethorphan), and CYP3A (nifedipine). The formation of the CYP-specific metabolites following co-incubation with various anastrozole concentrations was determined to establish IC50 and Ki values for these enzymes. While anastrozole did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 microM, this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with Ki values of 8, 10, and 10 microM, respectively. Dixon plots used to determine the Ki values for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic, indicating additional lower affinity Ki values. Major metabolites of anastrozole did not retain the ability to inhibit the metabolism of nifedipine (CYP3A). The results of this study indicate that, although anastrozole can inhibit CYP1A2, 2C9, and 3A-mediated catalytic activities, this compound would not be expected to cause clinically significant interactions with other CYP-metabolized drugs at physiologically relevant concentrations achieved during therapy with Arimidex (Zeneca, Ltd., Macclesfield, UK) 1-mg.
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    46. 46
      Gobbi, S.; Rampa, A.; Belluti, F.; Bisi, A. Nonsteroidal Aromatase Inhibitors for the Treatment of Breast Cancer: An Update. Anticancer Agents Med. Chem. 2014, 14 (1), 54– 65,  DOI: 10.2174/18715206113139990306
      46
      Nonsteroidal aromatase inhibitors for the treatment of breast cancer: an update
      Gobbi Silvia; Rampa Angela; Belluti Federica; Bisi Alessandra
      Anti-cancer agents in medicinal chemistry (2014), 14 (1), 54-65 ISSN:.
      Estrogens are known to be important in breast cancer growth in both pre- and post-menopausal women. Although circulating estrogen concentrations are very low after menopause, peripheral tissues generate sufficient concentrations to stimulate tumor growth. As aromatase is the rate-limiting enzyme in estrogen biosynthesis, inhibitors of this enzyme represent effective targeted therapy for breast cancer. Three compounds are now FDA approved and have become the first-choice endocrine drugs for postmenopausal breast cancer patients, since they are associated with superior activity and better general tolerability when compared with the estrogen receptor modulator tamoxifen. Nevertheless, some questions concerning the use of aromatase inhibitors for the treatment of breast cancer still need to be addressed, mainly related to their side-effects and the development of resistance, making research in this field still appealing. Many research groups, including our own, are still dealing with the search of new compounds that possess aromatase inhibitory properties. In this review an update of the latest achievements in the field of nonsteroidal aromatase inhibitors will be given.
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    47. 47
      Rotstein, D. M.; Kertesz, D. J.; Walker, K. A. M.; Swinney, D. C. Stereoisomers of Ketoconazole: Preparation and Biological Activity. J. Med. Chem. 1992, 35 (15), 2818– 2825,  DOI: 10.1021/jm00093a015
      47
      Stereoisomers of ketoconazole: preparation and biological activity
      Rotstein, David M.; Kertesz, Denis J.; Walker, Keith A. M.; Swinney, David C.
      Journal of Medicinal Chemistry (1992), 35 (15), 2818-25CODEN: JMCMAR; ISSN:0022-2623.
      The four stereoisomers of the antifungal agent ketoconazole, (2S,4R)-, (2R,4R)-, (2R,4S)-, and (2S,4S)-(imidazolylmethyl)phenyl{[(acetylpiperazinyl)phenoxy]methyl}dioxolanes I, were prepd. and evaluated for their selectivity in inhibiting a no. of cytochrome P 450 enzymes. Thus, (bromomethyl)phenyldioxolanes II condensed with 4-(N-acetylpiperazino)phenol and imidazole to give I. II were prepd. by bromination of 2',4'-dichloroacetophenone followed by reaction with (S)- and (R)-solketal tosylate. Large differences in selectivity among the isomers were obsd. for inhibition of the cytochromes P 450 involved in steroid biosynthesis, whereas little difference was obsd. for inhibition of those assocd. with hepatic drug metab. The cis-(2S,4R) and trans-(2R,4R) isomers are equipotent in inhibiting corticoid 11β-hydroxylase and much more effective than their antipodes. Little selectivity was obsd. for inhibition of cholesterol side chain cleavage or xenobiotic hydroxylases. These data indicate that the affinity of azoles for cytochrome P 450 enzymes involved in steroid synthesis is high dependent on the stereochem. of the entire mol., whereas binding to drug metabolizing enzymes is a less selective process.
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    48. 48
      Fleseriu, M.; Castinetti, F. Updates on the Role of Adrenal Steroidogenesis Inhibitors in Cushing’s Syndrome: A Focus on Novel Therapies. Pituitary 2016, 19 (6), 643– 653,  DOI: 10.1007/s11102-016-0742-1
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      Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies
      Fleseriu, Maria; Castinetti, Frederic
      Pituitary (2016), 19 (6), 643-653CODEN: PITUF9; ISSN:1386-341X. (Springer)
      A review. Purpose: Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approx. 25% of patients, esp. those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatol. CS is rare overall, and clin. studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. Methods: We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. Results: Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). Conclusions: The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.
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    49. 49
      Brixius-Anderko, S.; Scott, E. E. Structure of Human Cortisol-Producing Cytochrome P450 11B1 Bound to the Breast Cancer Drug Fadrozole Provides Insights for Drug Design. J. Biol. Chem. 2019, 294 (2), 453– 460,  DOI: 10.1074/jbc.RA118.006214
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      Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design
      Brixius-Anderko, Simone; Scott, Emily E.
      Journal of Biological Chemistry (2019), 294 (2), 453-460CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Human cytochrome P 450 11B1 (CYP11B1) is responsible for the final step generating the steroid hormone cortisol, which controls stress and immune responses and glucose homeostasis. CYP11B1 is a promising drug target to manage Cushing's disease, a disorder arising from excessive cortisol prodn. However, the design of selective inhibitors has been hampered because structural information for CYP11B1 is unavailable and the enzyme has high amino acid sequence identity (93%) to a closely related enzyme, the aldosterone-producing CYP11B2. Here the authors report the x-ray crystal structure of human CYP11B1 (at 2.1 Å resoln.) in complex with fadrozole, a racemic compd. normally used to treat breast cancer by inhibiting estrogen-producing CYP19A1. Comparison of fadrozole-bound CYP11B1 with fadrozole-bound CYP11B2 revealed that despite conservation of the active-site residues, the overall structures and active sites had structural rearrangements consistent with distinct protein functions and inhibition. Whereas fadrozole binds to both CYP11B enzymes by coordinating the heme iron, CYP11B2 binds to the R enantiomer of fadrozole, and CYP11B1 binds to the S enantiomer, each with distinct orientations and interactions. These results provide insights into the cross-reactivity of drugs across multiple steroidogenic cytochrome P 450 enzymes, provide a structural basis for understanding human steroidogenesis, and pave the way for the design of more selective inhibitors of each human CYP11B enzyme.
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    50. 50
      Brixius-Anderko, S.; Scott, E. E. Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design. Hypertension 2021, 78 (3), 751– 759,  DOI: 10.1161/HYPERTENSIONAHA.121.17615
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      Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design
      Brixius-Anderko, Simone; Scott, Emily E.
      Hypertension (2021), 78 (3), 751-759CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)
      Primary aldosteronism, the major form of secondary hypertension, develops due to excess steroid hormone aldosterone produced by aldosterone synthase, also known as cytochrome P 450 11B2. CYP11B2 is 93% identical to cortisol-producing CYP11B1, which makes it difficult to design selective drugs. LCI699 (Osilodrostat, Isturisa) was initially developed as a CYP11B2 inhibitor but due to poor selectivity was recently repurposed as the first Food and Drug Administration-approved drug for CYP11B1-mediated Cushing disease. Thus, there is still no effective therapeutic option targeting CYP11B2 for primary aldosteronism. Using a structure/function approach, aspects of LCI699 interaction with CYP11B2 were examd. to facilitate the design of more selective inhibitors. LCI699 effectively binds and inhibits CYP11B2. To det. the structural basis for this interaction, X-ray crystallog. was used to solve the structure of CYP11B2 bound to LCI699. LCI699 binds in the active site with its imidazole nitrogen coordinating the heme iron. LCI699 binding was compared with that of its analog fadrozole to both CYP11B enzymes. Comparison with the CYP11B1 structure reveals distinct CYP11B active site architectures which can be exploited to directed drug design. Exploiting structural differences between the CYP11B enzymes will promote the design of therapeutics for the treatment of primary aldosteronism targeting CYP11B2 while reducing undesirable side effects due to off-target CYP11B1 inhibition.
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    51. 51
      Strushkevich, N.; Gilep, A. A.; Shen, L.; Arrowsmith, C. H.; Edwards, A. M.; Usanov, S. A.; Park, H.-W. Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition. Mol. Endocrinol. 2013, 27 (2), 315– 324,  DOI: 10.1210/me.2012-1287
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      Structural insights into aldosterone synthase substrate specificity and targeted inhibition
      Strushkevich, Natallia; Gilep, Andrei A.; Shen, Limin; Arrowsmith, Cheryl H.; Edwards, Aled M.; Usanov, Sergey A.; Park, Hee-Won
      Molecular Endocrinology (2013), 27 (2), 315-324CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)
      Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure. Excess aldosterone levels can arise from dysregulation of the renin-angiotensin-aldosterone system and are implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (cytochrome P 450 11B2, CYP11B2) is the sole enzyme responsible for the prodn. of aldosterone in humans. Blocking of aldosterone synthesis by mediating aldosterone synthase activity is thus a recently emerging pharmacol. therapy for hypertension, yet a lack of structural information has limited this approach. Here, we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone and an inhibitor fadrozole. The structures reveal a hydrophobic cavity with specific features assocd. with corticosteroid recognition. The substrate binding mode, along with biochem. data, explains the high 11β-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation. The low processivity of aldosterone synthase with a high extent of intermediates release might be one of the mechanisms of controlled aldosterone prodn. from deoxycorticosterone. Although the active site pocket is lined by identical residues between CYP11B isoforms, most of the divergent residues that confer addnl. 18-oxidase activity of aldosterone synthase are located in the I-helix (vicinity of the O2 activation path) and loops around the H-helix (affecting an egress channel closure required for retaining intermediates in the active site). This intrinsic flexibility is also reflected in isoform-selective inhibitor binding. Fadrozole binds to aldosterone synthase in the R-configuration, using part of the active site cavity pointing toward the egress channel. The structural organization of aldosterone synthase provides crit. insights into the mol. mechanism of catalysis and enables rational design of more specific antihypertensive agents.
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    52. 52
      Pinzi, L.; Rastelli, G. Identification of Target Associations for Polypharmacology from Analysis of Crystallographic Ligands of the Protein Data Bank. J. Chem. Inf. Model. 2020, 60 (1), 372– 390,  DOI: 10.1021/acs.jcim.9b00821
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      Identification of Target Associations for Polypharmacology from Analysis of Crystallographic Ligands of the Protein Data Bank
      Pinzi, Luca; Rastelli, Giulio
      Journal of Chemical Information and Modeling (2020), 60 (1), 372-390CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      The design of a chem. entity that potently and selectively binds to a biol. target of therapeutic relevance has dominated the scene of drug discovery so far. However, recent findings suggest that multi-target ligands may be endowed with superior efficacy and be less prone to drug resistance. The Protein Data Bank (PDB) provides exptl. validated structural information about targets and bound ligands. Therefore, it represents a valuable source of information to help identifying active sites, understanding pharmacophore requirements, designing novel ligands, and inferring structure-activity relationships. In this study, we performed a large-scale anal. of the PDB by integrating different ligand-based and structure-based approaches, with the aim of identifying promising target assocns. for polypharmacol. based on reported crystal structure information. First, the 2D and 3D similarity profiles of the crystallog. ligands were evaluated using different ligand-based methods. Then, activity data of pairs of similar ligands binding to different targets were inspected by comparing structural information with bioactivity annotations reported in the ChEMBL, BindingDB, BindingMOAD, and PDBbind databases. Afterward, extensive docking screenings of ligands in the identified cross-targets were made in order to validate and refine the ligand-based results. Finally, the therapeutic relevance of the identified target combinations for polypharmacol. was evaluated from comparison with information on therapeutic targets reported in the Therapeutic Target Database (TTD). The results led to the identification of several target assocns. with high therapeutic potential for polypharmacol.
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    53. 53
      Hawkins, P. C. D.; Skillman, A. G.; Nicholls, A. Comparison of Shape-Matching and Docking as Virtual Screening Tools. J. Med. Chem. 2007, 50 (1), 74– 82,  DOI: 10.1021/jm0603365
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      Comparison of Shape-Matching and Docking as Virtual Screening Tools
      Hawkins, Paul C. D.; Skillman, A. Geoffrey; Nicholls, Anthony
      Journal of Medicinal Chemistry (2007), 50 (1), 74-82CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Ligand docking is a widely used approach in virtual screening. In recent years a large no. of publications have appeared in which docking tools are compared and evaluated for their effectiveness in virtual screening against a wide variety of protein targets. These studies have shown that the effectiveness of docking in virtual screening is highly variable due to a large no. of possible confounding factors. Another class of method that has shown promise in virtual screening is the shape-based, ligand-centric approach. Several direct comparisons of docking with the shape-based tool ROCS have been conducted using data sets from some of these recent docking publications. The results show that a shape-based, ligand-centric approach is more consistent than, and often superior to, the protein-centric approach taken by docking.
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    54. 54
      Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery. Nucleic Acids Res. 2012, 40 (D1), D1100– 1107,  DOI: 10.1093/nar/gkr777
      54
      ChEMBL: a large-scale bioactivity database for drug discovery
      Gaulton, Anna; Bellis, Louisa J.; Bento, A. Patricia; Chambers, Jon; Davies, Mark; Hersey, Anne; Light, Yvonne; McGlinchey, Shaun; Michalovich, David; Al-Lazikani, Bissan; Overington, John P.
      Nucleic Acids Research (2012), 40 (D1), D1100-D1107CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      ChEMBL is an Open Data database contg. binding, functional and ADMET information for a large no. of drug-like bioactive compds. These data are manually abstracted from the primary published literature on a regular basis, then further curated and standardized to maximize their quality and utility across a wide range of chem. biol. and drug-discovery research problems. Currently, the database contains 5.4 million bioactivity measurements for more than 1 million compds. and 5200 protein targets. Access is available through a web-based interface, data downloads and web services at: https://www.ebi.ac.uk/chembldb.
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    55. 55
      Gaulton, A.; Hersey, A.; Nowotka, M.; Bento, A. P.; Chambers, J.; Mendez, D.; Mutowo, P.; Atkinson, F.; Bellis, L. J.; Cibrián-Uhalte, E.; Davies, M.; Dedman, N.; Karlsson, A.; Magariños, M. P.; Overington, J. P.; Papadatos, G.; Smit, I.; Leach, A. R. The ChEMBL Database in 2017. Nucleic Acids Res. 2017, 45 (D1), D945– D954,  DOI: 10.1093/nar/gkw1074
      55
      The ChEMBL database in 2017
      Gaulton, Anna; Hersey, Anne; Nowotka, Micha-l; Bento, A. Patricia; Chambers, Jon; Mendez, David; Mutowo, Prudence; Atkinson, Francis; Bellis, Louisa J.; Cibrian-Uhalte, Elena; Davies, Mark; Dedman, Nathan; Karlsson, Anneli; Magarinos, Maria Paula; Overington, John P.; Papadatos, George; Smit, Ines; Leach, Andrew R.
      Nucleic Acids Research (2017), 45 (D1), D945-D954CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 and 2014 Nucleic Acids Research Database Issues. Since then, alongside the continued extn. of data from the medicinal chem. literature, new sources of bioactivity data have also been added to the database. These include: deposited data sets from neglected disease screening; crop protection data; drug metab. and disposition data and bioactivity data from patents. A no. of improvements and new features have also been incorporated. These include the annotation of assays and targets using ontologies, the inclusion of targets and indications for clin. candidates, addn. of metabolic pathways for drugs and calcn. of structural alerts. The ChEMBL data can be accessed via a web-interface, RDF distribution, data downloads and RESTful web-services.
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    56. 56
      Furet, P.; Batzl, C.; Bhatnagar, A.; Francotte, E.; Rihs, G.; Lang, M. Aromatase Inhibitors: Synthesis, Biological Activity, and Binding Mode of Azole-Type Compounds. J. Med. Chem. 1993, 36 (10), 1393– 1400,  DOI: 10.1021/jm00062a012
      56
      Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds
      Furet, P.; Batzl, C.; Bhatnagar, A.; Francotte, E.; Rihs, G.; Lang, M.
      Journal of Medicinal Chemistry (1993), 36 (10), 1393-400CODEN: JMCMAR; ISSN:0022-2623.
      The enantiomers of the potent nonsteroidal inhibitor of aromatase, fadrozole hydrochloride, I (R1 = 4-NCC6H4, R2 = H; R1 = H, R2 = 4-NCC6H4), have been sepd. and their abs. configuration detd. by x-ray crystallog. On the basis of a mol. modeling comparison of the active enantiomer I ((R1 = 4-NCC6H4, R2 = H) and one of the most potent steroidal inhibitors reported to date, (19R)-10-thiiranylestr-4-ene-3,17-dione, II, a model describing the relative binding modes of the azole-type and steroidal inhibitors of aromatase at the active site of the enzyme is proposed. It is suggested that the cyanophenyl moiety present in the most active azole inhibitors partially mimics the steroid backbone of the natural substrate for aromatase, androst-4-ene-3,17-dione. The synthesis and biol. testing of novel analogs of fadrozole used to define the accessible and nonaccessible vols. to ligands in the model of the active site of aromatase are reported. Thus, imidazole reacted with SOCl2 and 6-cyano-1-tetralone in CH2Cl2 to give imidazolylcyanotetralin III.
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    57. 57
      Meyers, K.; Cogan, D. A.; Burke, J.; Arenas, R.; Balestra, M.; Brown, N. F.; Chen, Z.; Cerny, M. A.; Clifford, H. E.; Colombo, F.; Fader, L.; Frederick, K. S.; Guo, X.; Goldberg, D.; Hornberger, K. R.; Kugler, S.; Lord, J.; Marshall, D. R.; Moss, N.; Parmentier, J.-H.; Richman, J. R.; Schmenk, J.; Weldon, S. M.; Yu, M.; Zhang, M. Dihydrobenzisoxazole-4-One Compounds Are Novel Selective Inhibitors of Aldosterone Synthase (CYP11B2) with in Vivo Activity. Bioorg. Med. Chem. Lett. 2018, 28 (5), 979– 984,  DOI: 10.1016/j.bmcl.2017.12.015
      57
      Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity
      Meyers, Kenneth; Cogan, Derek A.; Burke, Jennifer; Arenas, Raquel; Balestra, Michael; Brown, Nicholas F.; Cerny, Matthew A.; Clifford, Holly E.; Colombo, Federico; Fader, Lee; Frederick, Kosea S.; Guo, Xin; Hornberger, Keith R.; Kugler, Stanley; Lord, John; Marshall, Daniel R.; Moss, Neil; Richman, Jeremy R.; Schmenk, Jennifer; Weldon, Steven M.; Yu, Maolin; Zhang, Michael; Chen, Zhidong
      Bioorganic & Medicinal Chemistry Letters (2018), 28 (5), 979-984CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compds. are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a redn. of the isoxazole ring. While the enzyme responsible for the reductive metab. remains unknown, the rate of metab. could be attenuated by the addn. of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone prodn. without impacting plasma cortisol concns.
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    58. 58
      McGann, M. FRED Pose Prediction and Virtual Screening Accuracy. J. Chem. Inf. Model. 2011, 51 (3), 578– 596,  DOI: 10.1021/ci100436p
      58
      FRED Pose Prediction and Virtual Screening Accuracy
      McGann, Mark
      Journal of Chemical Information and Modeling (2011), 51 (3), 578-596CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Results of a previous docking study are reanalyzed and extended to include results from the docking program FRED and a detailed statistical anal. of both structure reprodn. and virtual screening results. FRED is run both in a traditional docking mode and in a hybrid mode that makes use of 16 the structure of a bound ligand in addn. to the protein structure to screen mols. This anal. shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next. Comparing methods, the difference in mean performance on DUD is found to be statistically significant (95% confidence) 61% of the time when using a global enrichment metric (AUC). Early enrichment metrics are found to have relatively poor statistical power, with 0.5% early enrichment only able to distinguish methods to 95% confidence 14% of the time.
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    59. 59
      Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural Basis for Androgen Specificity and Oestrogen Synthesis in Human Aromatase. Nature 2009, 457 (7226), 219– 223,  DOI: 10.1038/nature07614
      59
      Structural basis for androgen specificity and estrogen synthesis in human aromatase
      Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter
      Nature (London, United Kingdom) (2009), 457 (7226), 219-223CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Aromatase cytochrome P 450 is the only enzyme in vertebrates known to catalyze the biosynthesis of all estrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for estrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P 450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to estrone, 17β-estradiol and 17β,16α-estriol, resp. The first two steps are C19-Me hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochem. mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P 450 and P 450 in hormone biosynthetic pathways to be crystd. so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione mol. snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The mol. basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.
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    60. 60
      Yin, L.; Hu, Q.; Hartmann, R. W. Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks. J. Med. Chem. 2013, 56 (2), 460– 470,  DOI: 10.1021/jm301408t
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      Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks
      Yin, Lina; Hu, Qingzhong; Hartmann, Rolf W.
      Journal of Medicinal Chemistry (2013), 56 (2), 460-470CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concns. of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, i.e., a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compds. 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, esp. compd. 3p (I), which exhibited IC50 values of 32 and 41 nM for CYP19 and CYP11B2, resp., and a high selectivity toward CYP17 and CYP11B1. This compd. is considered as a candidate for further evaluation in vivo.
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    61. 61
      Meredith, E. L.; Ksander, G.; Monovich, L. G.; Papillon, J. P. N.; Liu, Q.; Miranda, K.; Morris, P.; Rao, C.; Burgis, R.; Capparelli, M.; Hu, Q.-Y.; Singh, A.; Rigel, D. F.; Jeng, A. Y.; Beil, M.; Fu, F.; Hu, C.-W.; LaSala, D. Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors. ACS Med. Chem. Lett. 2013, 4 (12), 1203– 1207,  DOI: 10.1021/ml400324c
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      Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors
      Meredith, Erik L.; Ksander, Gary; Monovich, Lauren G.; Papillon, Julien P. N.; Liu, Qian; Miranda, Karl; Morris, Patrick; Rao, Chang; Burgis, Robin; Capparelli, Michael; Hu, Qi-Ying; Singh, Alok; Rigel, Dean F.; Jeng, Arco Y.; Beil, Michael; Fu, Fumin; Hu, Chii-Whei; LaSala, Daniel
      ACS Medicinal Chemistry Letters (2013), 4 (12), 1203-1207CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathol. such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clin. candidate I, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compd. I was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol prodn. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
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    62. 62
      Bochevarov, A. D.; Harder, E.; Hughes, T. F.; Greenwood, J. R.; Braden, D. A.; Philipp, D. M.; Rinaldo, D.; Halls, M. D.; Zhang, J.; Friesner, R. A. Jaguar: A High-performance Quantum Chemistry Software Program with Strengths in Life and Materials Sciences. Int. J. Quantum Chem. 2013, 113 (18), 2110– 2142,  DOI: 10.1002/qua.24481
      62
      Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences
      Bochevarov, Art D.; Harder, Edward; Hughes, Thomas F.; Greenwood, Jeremy R.; Braden, Dale A.; Philipp, Dean M.; Rinaldo, David; Halls, Mathew D.; Zhang, Jing; Friesner, Richard A.
      International Journal of Quantum Chemistry (2013), 113 (18), 2110-2142CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)
      A review. Jaguar is an ab initio quantum chem. program that specializes in fast electronic structure predictions for mol. systems of medium and large size. Jaguar focuses on computational methods with reasonable computational scaling with the size of the system, such as d. functional theory (DFT) and local second-order Moller-Plesset perturbation theory. The favorable scaling of the methods and the high efficiency of the program make it possible to conduct routine computations involving several thousand MOs. This performance is achieved through a utilization of the pseudospectral approxn. and several levels of parallelization. The speed advantages are beneficial for applying Jaguar in biomol. computational modeling. Addnl., owing to its superior wave function guess for transition-metal-contg. systems, Jaguar finds applications in inorg. and bioinorg. chem. The emphasis on larger systems and transition metal elements paves the way toward developing Jaguar for its use in materials science modeling. The article describes the historical and new features of Jaguar, such as improved parallelization of many modules, innovations in ab initio pKa prediction, and new semiempirical corrections for nondynamic correlation errors in DFT. Jaguar applications in drug discovery, materials science, force field parameterization, and other areas of computational research are reviewed. Timing benchmarks and other results obtained from the most recent Jaguar code are provided. The article concludes with a discussion of challenges and directions for future development of the program. © 2013 Wiley Periodicals, Inc.
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    63. 63
      Nelson, D. R.; Zeldin, D. C.; Hoffman, S. M.; Maltais, L. J.; Wain, H. M.; Nebert, D. W. Comparison of Cytochrome P450 (CYP) Genes from the Mouse and Human Genomes, Including Nomenclature Recommendations for Genes, Pseudogenes and Alternative-Splice Variants. Pharmacogenetics 2004, 14 (1), 1– 18,  DOI: 10.1097/00008571-200401000-00001
      63
      Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants
      Nelson, David R.; Zeldin, Darryl C.; Hoffman, Susan M. G.; Maltais, Lois J.; Wain, Hester M.; Nebert, Daniel W.
      Pharmacogenetics (2004), 14 (1), 1-18CODEN: PHMCEE; ISSN:0960-314X. (Lippincott Williams & Wilkins)
      A review. Completion of both the mouse and human genome sequences in the private and public sectors has prompted comparison between the two species at multiple levels. This review summarizes the cytochrome P 450 (CYP) gene superfamily. For the first time, we have the ability to compare complete sets of CYP genes from two mammals. Use of the mouse as a model mammal, and as a surrogate for human biol., assumes reasonable similarity between the two. It is therefore of interest to catalog the genetic similarities and differences, and to clarify the limits of extrapolation from mouse to human. Data-mining methods have been used to find all the mouse and human CYP sequences; this includes 102 putatively functional genes and 88 pseudogenes in the mouse, and 57 putatively functional genes and 58 pseudogenes in the human. Comparison is made between all these genes, esp. the seven main CYP gene clusters. The seven CYP clusters are greatly expanded in the mouse with 72 functional genes vs. only 27 in the human, while many pseudogenes are present; presumably this phenomenon will be seen in many other gene superfamily clusters. Complete identification of all pseudogene sequences is likely to be clin. important, because some of these highly similar exons can interfere with PCR-based genotyping assays. A naming procedure for each of four categories of CYP pseudogenes is proposed, and we encourage various gene nomenclature committees to consider seriously the adoption and application of this pseudogene nomenclature system.
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    64. 64
      Hare, S. H.; Harvey, A. J. mTOR Function and Therapeutic Targeting in Breast Cancer. Am. J. Cancer Res. 2017, 7 (3), 383– 404
      64
      mTOR function and therapeutic targeting in breast cancer
      Hare, Stephen H.; Harvey, Amanda J.
      American Journal of Cancer Research (2017), 7 (3), 383-404CODEN: AJCRFT; ISSN:2156-6976. (e-Century Publishing Corp.)
      The mTOR pathway was discovered in the late 1970s after the compd. and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy while mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer. This can involve mutations in mTOR itself but more commonly, in breast cancer, this is related to an increase in activity of ErbB family receptors or alterations and mutations of PI3K signaling. Rapamycin and its analogs (rapalogues) bind to the intercellular receptor FKBP12, and then predominantly inhibit mTORC1 signaling via an allosteric mechanism. Research has shown that inhibition of mTOR is a useful strategy in tackling cancers, with it acting to slow tumor growth and limit the spread of a cancer. Rapalogues have now made their way into the clinic with the rapalogue everolimus (RAD-001/Afinitor) approved for use in conjunction with exemestane, in post-menopausal breast cancer patients with advanced disease who are HER-2 neg. (normal expression), hormone receptor pos. and whose prior treatment with non-steroidal aromatase inhibitors has failed. Testing across multiple trials has proven that everolimus and other rapalogues are a viable way of treating certain types of cancer. However, rapalogues have shown some drawbacks both in research and clin., with their use often activating feedback pathways that counter their usefulness. As such, new types of inhibitors are being explored that work via different mechanisms, including inhibitors that are ATP competitive with mTOR and which act to perturb signaling from both mTOR complexes.
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    65. 65
      Hadizadeh, F.; Shafiee, A.; Kazemi, R.; Mohammadi, M. Synthesis of 4-(1-Phenylmethyl-5-Imidazolyl)-1,4-Dihydropyridines as Calcium Channel Antagonists; NISCAIR-CSIR: India, 2002; vol 41B (12), pp 2679– 2682.
      There is no corresponding record for this reference.
    66. 66
      Millet, R.; Domarkas, J.; Houssin, R.; Gilleron, P.; Goossens, J.-F.; Chavatte, P.; Logé, C.; Pommery, N.; Pommery, J.; Hénichart, J.-P. Potent and Selective Farnesyl Transferase Inhibitors. J. Med. Chem. 2004, 47 (27), 6812– 6820,  DOI: 10.1021/jm030502y
      66
      Potent and Selective Farnesyl Transferase Inhibitors
      Millet, Regis; Domarkas, Juozas; Houssin, Raymond; Gilleron, Pauline; Goossens, Jean-Francois; Chavatte, Philippe; Loge, Cedric; Pommery, Nicole; Pommery, Jean; Henichart, Jean-Pierre
      Journal of Medicinal Chemistry (2004), 47 (27), 6812-6820CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compds. possess an N-(4-piperidinyl)benzamide scaffold mimicking A1A2 residue. Extensive exploration of structure-activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC50 = 4.60 nM on isolated enzyme, EC50 = 20.0 nM for growth inhibition on a tumor cell line). The mol. docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
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    67. 67
      Berthold, M. R.; Cebron, N.; Dill, F.; Gabriel, T. R.; Kötter, T.; Meinl, T.; Ohl, P.; Sieb, C.; Thiel, K.; Wiswedel, B. KNIME: The Konstanz Information Miner. In Data Analysis, Machine Learning and Applications; Studies in Classification, Data Analysis, and Knowledge Organization; Preisach, C.; Burkhardt, H.; Schmidt-Thieme, L.; Decker, R., Eds.; Springer: Berlin, Heidelberg, 2008; pp 319– 326.
      There is no corresponding record for this reference.
    68. 68
      Schrödinger Release 2018–3: LigPrep; Schrödinger, LLC: New York, NY, 2018.
      There is no corresponding record for this reference.
    69. 69
      Hawkins, P. C. D.; Skillman, A. G.; Warren, G. L.; Ellingson, B. A.; Stahl, M. T. Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database. J. Chem. Inf. Model. 2010, 50 (4), 572– 584,  DOI: 10.1021/ci100031x
      69
      Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database
      Hawkins, Paul C. D.; Skillman, A. Geoffrey; Warren, Gregory L.; Ellingson, Benjamin A.; Stahl, Matthew T.
      Journal of Chemical Information and Modeling (2010), 50 (4), 572-584CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Here, we present the algorithm and validation for OMEGA, a systematic, knowledge-based conformer generator. The algorithm consists of three phases: assembly of an initial 3D structure from a library of fragments; exhaustive enumeration of all rotatable torsions using values drawn from a knowledge-based list of angles, thereby generating a large set of conformations; and sampling of this set by geometric and energy criteria. Validation of conformer generators like OMEGA has often been undertaken by comparing computed conformer sets to exptl. mol. conformations from crystallog., usually from the Protein Databank (PDB). Such an approach is fraught with difficulty due to the systematic problems with small mol. structures in the PDB. Methods are presented to identify a diverse set of small mol. structures from cocomplexes in the PDB that has maximal reliability. A challenging set of 197 high quality, carefully selected ligand structures from well-solved models was obtained using these methods. This set will provide a sound basis for comparison and validation of conformer generators in the future. Validation results from this set are compared to the results using structures of a set of druglike mols. extd. from the Cambridge Structural Database (CSD). OMEGA is found to perform very well in reproducing the crystallog. conformations from both these data sets using two complementary metrics of success.
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    70. 70
      Pinzi, L.; Caporuscio, F.; Rastelli, G. Selection of Protein Conformations for Structure-Based Polypharmacology Studies. Drug Discovery Today 2018, 23 (11), 1889– 1896,  DOI: 10.1016/j.drudis.2018.08.007
      70
      Selection of protein conformations for structure-based polypharmacology studies
      Pinzi, Luca; Caporuscio, Fabiana; Rastelli, Giulio
      Drug Discovery Today (2018), 23 (11), 1889-1896CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
      A review. Several drugs exert their therapeutic effect through the modulation of multiple targets. Structure-based approaches hold great promise for identifying compds. with the desired polypharmacol. profiles. These methods use knowledge of the protein binding sites to identify stereoelectronically complementary ligands. The selection of the most suitable protein conformations to be used in the design process is vital, esp. for multitarget drug design in which the same ligand has to be accommodated in multiple binding pockets. Herein, we focus on currently available techniques for the selection of the most suitable protein conformations for multitarget drug design, compare the potential advantages and limitations of each method, and comment on how their combination could help in polypharmacol. drug design.
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    71. 71
      Pinzi, L.; Rastelli, G. Molecular Docking: Shifting Paradigms in Drug Discovery. Int. J. Mol. Sci. 2019, 20 (18), 4331,  DOI: 10.3390/ijms20184331
      71
      Molecular docking: shifting paradigms in drug discovery
      Pinzi, Luca; Rastelli, Giulio
      International Journal of Molecular Sciences (2019), 20 (18), 4331CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      A review. Mol. docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compds. of therapeutic interest, predicting ligand-target interactions at a mol. level, or delineating structure-activity relationships (SAR), without knowing a priori the chem. structure of other target modulators. Although it was originally developed to help understanding the mechanisms of mol. recognition between small and large mols., uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how mol. docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacol., drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVCns70%253D&md5=9ed9e680a89538b1ef1f11f6cd2b7e68
    72. 72
      Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. J. Comput. Aided Mol. Des. 2013, 27 (3), 221– 234,  DOI: 10.1007/s10822-013-9644-8
      72
      Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments
      Madhavi Sastry, G.; Adzhigirey, Matvey; Day, Tyler; Annabhimoju, Ramakrishna; Sherman, Woody
      Journal of Computer-Aided Molecular Design (2013), 27 (3), 221-234CODEN: JCADEQ; ISSN:0920-654X. (Springer)
      Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepd. prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove at. clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addn., ligands must be prepd. to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system prepn. is generally accepted in the field, an extensive study of the prepn. steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in prepg. a system for virtual screening. We first explore a large no. of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper prepn. and that neglecting certain steps of the prepn. process produces a systematic degrdn. in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the prepn. that impact database enrichment. While the work presented here was performed with the Protein Prepn. Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.3c00183.

    • Results of the similarity estimations performed with the LigAdvisor Web server; results of the similarity estimations performed with respect to compounds with activity annotation on CYP19A1, CYP11B2, and CYP11B1, reported in the DrugBank, PDB, and ChEMBL databases; docking scores of the investigated compounds into the PDB crystal structures 3EQM (CYP19A1), 6M7X (CYP11B1), and 4FDH (CYP11B2); binding mode predicted for (S)- and (R)-fadrozole into the CYP19A1 binding site (PDB ID: 3EQM); titration curves of compound X21 against CYP19A1, CYP1A2, and CYP3A4, with their respective controls; antiproliferative in vitro activity of fadrozole on human MCF-7 (Estrogen Receptor+) at 24, 48, and 72 h; and titration curves of compound X21 and the reference compounds E-4031 and tetrodoxin, against hERG and Nav1.5 (manual patch clamp assays), respectively (PDF)


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