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. 2022 Nov 1:75:128951.
doi: 10.1016/j.bmcl.2022.128951. Epub 2022 Aug 27.

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

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

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

Chetan Padmakar Darne et al. Bioorg Med Chem Lett. .

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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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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