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ACS Med Chem Lett. 2015 Dec 2;7(1):40-5. doi: 10.1021/acsmedchemlett.5b00310. eCollection 2016 Jan 14.

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

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1
Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.

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.

KEYWORDS:

CYP11B1; CYP17A1; CYP21A2; Prostate cancer; benzimidazoles; cortisol; lyase

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