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

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

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: upender.velaparthi@bms.com.
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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