title: (+)-(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.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. isao.kinoyama@jp.astellas.com
authors.forename: Isao
authors.initials: I
authors.lastname: Kinoyama
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Toyoshima
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nozawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kamikubo
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Samizu
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawanimani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Noritaka
authors.initials: N
authors.lastname: Hamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koutoku
authors.forename: Takashi
authors.initials: T
authors.lastname: Furutani
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudoh
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000726:Androgen Antagonists / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood; D014018:Tissue Distribution; D014158:Transcription, Genetic
chemical_list: C508803:4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-N-(6-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxamide; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D011944:Receptors, Androgen; D013739:Testosterone