Bicyclic Substituted Hydroxyphenylmethanones as Novel Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1) for the Treatment of Estrogen-Dependent Diseases
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- 作者：Alexander Oster ; Stefan Hinsberger ; Ruth Werth ; Sandrine Marchais-Oberwinkler ; Martin Frotscher ; Rolf W. Hartmann
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：November 25, 2010
- 年：2010
- 卷：53
- 期：22
- 页码：8176-8186
- 全文大小：961K
- 年卷期：v.53,no.22(November 25, 2010)
- ISSN：1520-4804
文摘
Estradiol (E2), the most important estrogen in humans, is involved in the initiation and progression of estrogen-dependent diseases such as breast cancer and endometriosis. Its local production in the target cell is regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes E2-formation by reduction of the weak estrogen estrone (E1). Because the enzyme is expressed in the diseased tissues, inhibition of 17β-HSD1 is considered as a promising therapy for the treatment of estrogen-dependent diseases. For the development of novel inhibitors, a structure- and ligand-based design strategy was applied, resulting in bicyclic substituted hydroxyphenylmethanones. In vitro testing revealed high inhibitory potencies toward human placental 17β-HSD1. Compounds were further evaluated with regard to selectivity (17β-HSD2, estrogen receptors ERα and ERβ), intracellular activity (T47D cells), and metabolic stability. The most promising compounds, 14 and 15, showed IC50 values in the low nanomolar range in the cell-free and cellular assays (8−27 nM), more than 30-fold selectivity toward 17β-HSD2 and no affinity toward the ERs. The data obtained make these inhibitors interesting candidates for further preclinical evaluation.