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Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer.

ABSTRACT: Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

SUBMITTER: Huang A

PROVIDER: S-EPMC4716597 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer.

Huang Audris A Jayaraman Lata L Fura Aberra A Vite Gregory D GD Trainor George L GL Gottardis Marco M MM Spires Thomas E TE Spires Vanessa M VM Rizzo Cheryl A CA Obermeier Mary T MT Elzinga Paul A PA Todderud Gordon G Fan Yi Y Newitt John A JA Beyer Sophie M SM Zhu Yongxin Y Warrack Bethanne M BM Goodenough Angela K AK Tebben Andrew J AJ Doweyko Arthur M AM Gold David L DL Balog Aaron A

ACS medicinal chemistry letters 20151202 1

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoi ...[more]

PMID: 26819663

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