1. The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer
- Author
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Chetan Padmakar Darne, Upender Velaparthi, Mark Saulnier, David Frennesson, Peiying Liu, Audris Huang, John Tokarski, Aberra Fura, Thomas Spires, John Newitt, Vanessa M. Spires, Mary T. Obermeier, Paul A. Elzinga, Marco M. Gottardis, Lata Jayaraman, Gregory D. Vite, and Aaron Balog
- Subjects
Male ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Lyases ,Prostatic Neoplasms ,Steroid 17-alpha-Hydroxylase ,Androgen Antagonists ,Biochemistry ,Xenobiotics ,Prostatic Neoplasms, Castration-Resistant ,Mineralocorticoids ,Drug Discovery ,Molecular Medicine ,Humans ,Testosterone ,Enzyme Inhibitors ,Molecular Biology ,Glucocorticoids - 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.
- Published
- 2022