title: N-Arylpiperazine-1-carboxamide derivatives: a novel series of orally active nonsteroidal androgen receptor antagonists.
abstract: A novel series of N-arylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Reporter assays indicated that trans-2,5-dimethylpiperazine derivatives are potent AR antagonists, and in this series trans-N-4-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide (18 g, YM-175735) exhibited the most potent antiandrogenic activity. Compared to bicalutamide, YM-175735 is an approximately 4-fold stronger AR antagonist and has slightly increased antiandrogenic activity, suggesting that YM-175735 may be useful in the treatment of prostate cancer.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki. kinoyama@yamanouchi.co.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Kinoyama
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawaminami
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nozawa
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
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000138:chemical synthesis* / Q000494:pharmacology*; D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000818:Animals; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009919:Orchiectomy; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011467:Prostate / Q000187:drug effects / Q000254:growth & development; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D007202:Indicators and Reagents; D010879:Piperazines; D000620:Aminoimidazole Carboxamide; D013739:Testosterone