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

17 beta-Hydroxystcroid dehydrogenase type 1 (17 beta-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 alpha (ER alpha). Because of the overexpression of 17 beta-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 17 beta-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 17 beta-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 (17 beta-HSD2, ER alpha) and excellent pharmacokinetic properties after peroral application to rats.