Discovery of an orally-active nonsteroidal androgen receptor pure antagonist and the structure-activity relationships of its derivatives.
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).
Tachibana
Kazutaka
K
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan. tachibanakzt@chugai-pharm.co.jp
Imaoka
Ikuhiro
I
Shiraishi
Takuya
T
Yoshino
Hitoshi
H
Nakamura
Mitsuaki
M
Ohta
Masateru
M
Kawata
Hiromitsu
H
Taniguchi
Kenji
K
Ishikura
Nobuyuki
N
Tsunenari
Toshiaki
T
Saito
Hidemi
H
Nagamuta
Masahiro
M
Nakagawa
Toshito
T
Takanashi
Kenji
K
Onuma
Etsuro
E
Sato
Haruhiko
H
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
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D007202:Indicators and Reagents; D013867:Thiohydantoins