2. Academic Validation
  3. (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist

(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)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. doi: 10.1021/jm050293c.
Isao Kinoyama 1,  Nobuaki Taniguchi,  Akira Toyoshima,  Eisuke Nozawa,  Takashi Kamikubo,  Masakazu Imamura,  Akira Matsuhisa,  Kiyohiro Samizu,  Eiji Kawanimani,  Tatsuya Niimi,  Noritaka Hamada,  Hiroshi Koutoku,  Takashi Furutani,  Masafumi Kudoh,  Minoru Okada,  Mitsuaki Ohta,  Shin-ichi Tsukamoto
Affiliations

Affiliation

  • 1 Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. isao.kinoyama@jp.astellas.com
PMID: 16420057 DOI: 10.1021/jm050293c
Abstract

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-(trifluoromethyl)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.

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