Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.
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.
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
Emura
Takashi
T
Kodama
Hirohumi
H
Furuta
Yoshiyuki
Y
Kato
Nobuaki
N
Nakamura
Mitsuaki
M
Ohta
Masateru
M
Taniguchi
Kenji
K
Ishikura
Nobuyuki
N
Nagamuta
Masahiro
M
Onuma
Etsuro
E
Sato
Haruhiko
H
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
D059002:Androgen Receptor Antagonists; D013196:Dihydrotestosterone