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.
Audris Huang  1 ,  Lata Jayaraman  1 ,  Aberra Fura  1 ,  Gregory D Vite  1 ,  George L Trainor  1 ,  Marco M Gottardis  1 ,  Thomas E Spires  1 ,  Vanessa M Spires  1 ,  Cheryl A Rizzo  1 ,  Mary T Obermeier  1 ,  Paul A Elzinga  1 ,  Gordon Todderud  1 ,  Yi Fan  1 ,  John A Newitt  1 ,  Sophie M Beyer  1 ,  Yongxin Zhu  1 ,  Bethanne M Warrack  1 ,  Angela K Goodenough  1 ,  Andrew J Tebben  1 ,  Arthur M Doweyko  1 ,  David L Gold  1 ,  Aaron Balog  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
PMID: 26819663 DOI: 10.1021/acsmedchemlett.5b00310
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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