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

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.

ACS medicinal chemistry letters. 2015 Dec 02*** epublish ***

Audris Huang, Lata Jayaraman, Aberra Fura, Gregory D Vite, George L Trainor, Marco M Gottardis, Thomas E Spires, Vanessa M Spires, Cheryl A Rizzo, Mary T Obermeier, Paul A Elzinga, Gordon Todderud, Yi Fan, John A Newitt, Sophie M Beyer, Yongxin Zhu, Bethanne M Warrack, Angela K Goodenough, Andrew J Tebben, Arthur M Doweyko, David L Gold, Aaron Balog

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

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