title: Discovery of an orally-active nonsteroidal androgen receptor pure antagonist and the structure-activity relationships of its derivatives.
abstract: The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan. tachibanakzt@chugai-pharm.co.jp
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tachibana
authors.forename: Ikuhiro
authors.initials: I
authors.lastname: Imaoka
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masateru
authors.initials: M
authors.lastname: Ohta
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kawata
authors.forename: Kenji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishikura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsunenari
authors.forename: Hidemi
authors.initials: H
authors.lastname: Saito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagamuta
authors.forename: Toshito
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
authors.forename: Etsuro
authors.initials: E
authors.lastname: Onuma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D017930:Genes, Reporter / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D012669:Seminal Vesicles / Q000187:drug effects; D013329:Structure-Activity Relationship; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D007202:Indicators and Reagents; D013867:Thiohydantoins