The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer. (1st November 2022)

• Record Type: Journal Article
• Authors: Padmakar Darne, Chetan; Velaparthi, Upender; Saulnier, Mark; Frennesson, David; Liu, Peiying; Huang, Audris; Tokarski, John; Fura, Aberra; Spires, Thomas; Newitt, John; Spires, Vanessa M.; Obermeier, Mary T.; Elzinga, Paul A.; Gottardis, Marco M.; Jayaraman, Lata; Vite, Gregory D.; Balog, Aaron
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 75(2022)
• Publication Date: 2022-11-01
• Subjects: Castration-resistant prostate cancer (CRPC) -- CYP17A1 -- CYP11B1 -- CYP21A2 -- CYP1A2 -- Lyase -- Hydroxylase -- Glucocorticoids -- Mineralocorticoids -- abiraterone acetate (AA) -- Aza-indazole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128951
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.