New Insights into the SAR and Binding Modes of Bis(hydroxyphenyl)thiophenes and -benzenes: Influence of Additional Substituents on 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1) Inhibito

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• 作者：Emmanuel Bey ; Sandrine Marchais-Oberwinkler ; Matthias Negri ; Patricia Kruchten ; Alexander Oster ; Tobias Klein ; Alessandro Spadaro ; Ruth Werth ; Martin Frotscher ; Barbara Birk ; Rolf W. Hartmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 12, 2009
• 年：2009
• 卷：52
• 期：21
• 页码：6724-6743
• 全文大小：1325K
• 年卷期：v.52,no.21(November 12, 2009)
• ISSN：1520-4804

文摘

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor α (ERα). Because of the overexpression of 17β-HSD1 in mammary tumors, this enzyme should be an attractive target for the treatment of estrogen-dependent pathologies. Recently, we have reported on a series of potent 17β-HSD1 inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In this paper, different substituents are introduced into the core structure and the biological properties of the corresponding inhibitors are evaluated. Computational methods and analysis of different X-rays of 17β-HSD1 lead to identification of two different binding modes for these inhibitors. The fluorine compound 23 exhibits an IC₅₀ of 8 nM and is the most potent nonsteroidal inhibitor described so far. It also shows a high selectivity (17β-HSD2, ERα) and excellent pharmacokinetic properties after peroral application to rats.