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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) Inhibitory Activity and Selectivity

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journal contribution
posted on 2009-11-12, 00:00 authored by Emmanuel Bey, Sandrine Marchais-Oberwinkler, Matthias Negri, Patricia Kruchten, Alexander Oster, Tobias Klein, Alessandro Spadaro, Ruth Werth, Martin Frotscher, Barbara Birk, Rolf W. Hartmann
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.