(+)-(2R,5S)-4-4-Cyano-3-(trifluoromethyl)phenyl-2,5-dimethyl-N-6-(trifluoromethyl)pyridin-3-ylpiperazine-l-carboxamide (YM580) as an Orally Potent and Peripherally Selective Nonsteroidal Androgen Receptor Antagonist

摘要

A novel series of trans-N-aryl-2,5-dimethylpiperazine-l-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated.Pharmacological assays indicated that compound 33 was a potent AR antagonist,and subsequent optical resolution provided (+)-(2R,5S)-4-4-cyano-3-(trifluoromethyl)phenyl-2,5-dimethyl-N-6-(trifluoromethyl)pyridin-3-ylpip-erazine-1-carboxamide (33a,YM580) which exhibited the most potent antiandrogenic activity.Unlike bicalutamide,compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED_(50) = 2.2 mg/kg/day),and induced the maximum antiandrogenic effect,comparable to that of surgical castration,without significantly affecting serum testosterone levels.Compound 33a is a promising clinical candidate for prostate cancer monotherapy.