Novel selective anti-androgens with a diphenylpentane skeleton

Keisuke Maruyama, Tomomi Noguchi-Yachide, Kazuyuki Sugita, Yuichi Hashimoto, Minoru Ishikawa

研究成果: Article査読

20 被引用数 (Scopus)

抄録

We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC 50: 0.13 μM) than clinically used anti-androgen bicalutamide (IC50: 0.67 μM) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds.

本文言語English
ページ(範囲)6661-6666
ページ数6
ジャーナルBioorganic and Medicinal Chemistry Letters
20
22
DOI
出版ステータスPublished - 2010 11 15
外部発表はい

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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