2. Academic Validation
  3. Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships

Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships

  • Bioorg Med Chem. 2007 Jan 1;15(1):174-85. doi: 10.1016/j.bmc.2006.09.072.
Kazutaka Tachibana 1,  Ikuhiro Imaoka,  Hitoshi Yoshino,  Takashi Emura,  Hirohumi Kodama,  Yoshiyuki Furuta,  Nobuaki Kato,  Mitsuaki Nakamura,  Masateru Ohta,  Kenji Taniguchi,  Nobuyuki Ishikura,  Masahiro Nagamuta,  Etsuro Onuma,  Haruhiko Sato
Affiliations

Affiliation

  • 1 Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. tachibanakzt@chugai-pharm.co.jp
PMID: 17064916 DOI: 10.1016/j.bmc.2006.09.072
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.

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