title: Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists.
abstract: 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.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, 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: Hitoshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kato
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: Masahiro
authors.initials: M
authors.lastname: Nagamuta
authors.forename: Etsuro
authors.initials: E
authors.lastname: Onuma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
mesh_terms: 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