| 16420057 |
Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T, Hamada N, Koutoku H, Furutani T, Kudoh M, Okada M, Ohta M, Tsukamoto S: (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl) phenyl]-2,5-dimethyl-N-[6-(trifl uoromethyl) pyridin-3- yl] piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist. J Med Chem. 2006 Jan 26;49(2):716-26.
A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-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-(trifl uoromethyl) pyridin-3-yl] piperazine-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. |
32(0,1,1,2) |