The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer

  • Bioorg Med Chem Lett. 2022 Nov 1:75:128951. doi: 10.1016/j.bmcl.2022.128951.
Chetan Padmakar Darne  1 ,  Upender Velaparthi  2 ,  Mark Saulnier  1 ,  David Frennesson  1 ,  Peiying Liu  1 ,  Audris Huang  1 ,  John Tokarski  1 ,  Aberra Fura  1 ,  Thomas Spires  1 ,  John Newitt  1 ,  Vanessa M Spires  1 ,  Mary T Obermeier  1 ,  Paul A Elzinga  1 ,  Marco M Gottardis  1 ,  Lata Jayaraman  1 ,  Gregory D Vite  1 ,  Aaron Balog  1
Affiliations
  • 1. Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
  • 2. Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States. Electronic address: [email protected].
PMID: 36031020 DOI: 10.1016/j.bmcl.2022.128951
Abstract

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate Cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.

Keywords
Aza-indazole; CYP11B1; CYP17A1; CYP1A2; CYP21A2; Castration-resistant prostate cancer (CRPC); Glucocorticoids; Hydroxylase; Lyase; Mineralocorticoids; abiraterone acetate (AA).
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