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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