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

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

doi:10.1021/acsmedchemlett.5b00310

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

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

Authors

Audris Huang¹, Lata Jayaraman¹, Aberra Fura¹, Gregory D Vite¹, George L Trainor¹, Marco M Gottardis¹, Thomas E Spires¹, Vanessa M Spires¹, Cheryl A Rizzo¹, Mary T Obermeier¹, Paul A Elzinga¹, Gordon Todderud¹, Yi Fan¹, John A Newitt¹, Sophie M Beyer¹, Yongxin Zhu¹, Bethanne M Warrack¹, Angela K Goodenough¹, Andrew J Tebben¹, Arthur M Doweyko¹, David L Gold¹, Aaron Balog¹

Affiliation

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.