title: Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.
abstract: A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.
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: Takashi
authors.initials: T
authors.lastname: Emura
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Kodama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Furuta
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: 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; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D013196:Dihydrotestosterone