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

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 gluco-corticoid levels in cynomologous monkeys in a 1-day PK/PD study.

Automated summary

In this study, the discovery of BMS-737 as a potent small molecule inhibitor for the treatment of castration-resistant prostate cancer (CRPC) is reported. The inhibitor demonstrates high selectivity for CYP17 lyase over CYP17 hydroxylase, with a clean xenobiotic CYP profile. Extensive structure-activity relationship studies led to the identification of BMS-737, which showed significant lowering of testosterone in animal experiments.