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

weak estrogen estrone (E1) into the highly potent 17 beta-estradiol (E2). As 17 beta-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-de pendent diseases. Recently, we reported on bis(hydroxyphenyl)azoles as a new class of potent inhibitors of 17 beta-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 17 beta-HSD1 and selectivity with regard to 17 beta-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 IC50 value of 840 nM and a reasonable selectivity towards 17 beta-HSD2. (C) 2008 Elsevier Ireland Ltd. All rights reserved.