Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17尾-Hydroxysteroid Dehydrogenase 2 Inhibitors

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• 作者：Anna Vuorinen ; Roger Engeli ; Arne Meyer ; Fabio Bachmann ; Ulrich J. Griesser ; Daniela Schuster ; Alex Odermatt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5995-6007
• 全文大小：562K
• ISSN：1520-4804

文摘

17尾-Hydroxysteroid dehydrogenase 2 (17尾-HSD2) catalyzes the inactivation of estradiol into estrone. This enzyme is expressed only in a few tissues, and therefore its inhibition is considered as a treatment option for osteoporosis to ameliorate estrogen deficiency. In this study, ligand-based pharmacophore models for 17尾-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17尾-HSD2 inhibition. Seven compounds inhibited 17尾-HSD2 with low micromolar IC₅₀ values. To investigate structure鈥揳ctivity relationships (SAR), 30 more derivatives of the original hits were tested. The three most potent hits, 12, 22, and 15, had IC₅₀ values of 240 nM, 1 渭M, and 1.5 渭M, respectively. All but 1 of the 13 identified inhibitors were selective over 17尾-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17尾-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs.