2. Academic Validation
  3. Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer

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

Affiliation

  • 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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