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Mol Cell Endocrinol. 2009 Mar 25;301(1-2):212-5. doi: 10.1016/j.mce.2008.09.012. Epub 2008 Sep 19.

The role of the heterocycle in bis(hydroxyphenyl)triazoles for inhibition of 17beta-Hydroxysteroid Dehydrogenase (17beta-HSD) type 1 and type 2.

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8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbr├╝cken, Germany.


17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of the weak estrogen estrone (E1) into the highly potent 17beta-estradiol (E2). As 17beta-HSD1 is often overexpressed in mammary tumors and endometriosis, the selective inhibition of this enzyme is discussed as a promising approach for the treatment of estrogen-dependent diseases. Recently, we reported on bis(hydroxyphenyl)azoles as a new class of potent inhibitors of 17beta-HSD1. In this paper, we focused on bis(hydroxyphenyl)triazoles. The influence of nitrogens on the potency as well as the space available around the heterocycle was investigated. Substituents were introduced on the triazole core in order to establish additional interactions with the enzyme active site. The compounds were evaluated for activity towards 17beta-HSD1 and selectivity with regard to 17beta-HSD2, the enzyme which is responsible for the deactivation of E2 into E1. 3-[4-(4-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]phenol (3) was the most active compound discovered in this study with an IC(50) value of 840nM and a reasonable selectivity towards 17beta-HSD2.

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