Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists.
Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
Tachibana
Kazutaka
K
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. tachibanakzt@chugai-pharm.co.jp
Imaoka
Ikuhiro
I
Yoshino
Hitoshi
H
Kato
Nobuaki
N
Nakamura
Mitsuaki
M
Ohta
Masateru
M
Kawata
Hiromitsu
H
Taniguchi
Kenji
K
Ishikura
Nobuyuki
N
Nagamuta
Masahiro
M
Onuma
Etsuro
E
Sato
Haruhiko
H
D059002:Androgen Receptor Antagonists; D000818:Animals; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship