(+)-(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.
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.
Kinoyama
Isao
I
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. isao.kinoyama@jp.astellas.com
Taniguchi
Nobuaki
N
Toyoshima
Akira
A
Nozawa
Eisuke
E
Kamikubo
Takashi
T
Imamura
Masakazu
M
Matsuhisa
Akira
A
Samizu
Kiyohiro
K
Kawanimani
Eiji
E
Niimi
Tatsuya
T
Hamada
Noritaka
N
Koutoku
Hiroshi
H
Furutani
Takashi
T
Kudoh
Masafumi
M
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
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
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