Triazole ring-opening leads to the discovery of potent nonsteroidal 17β-hydroxysteroid dehydrogenase type 2 inhibitors

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes the oxidation of the highly potent steroids: the estrogen estradiol (E2) and the androgen testosterone (T) to the less active estrone and androstenedione, respectively. Inhibition of this enzyme may help maintain the local E2 level in bone tissue when the circulating E2 level drops and is therefore a novel and promising approach for the treatment of osteoporosis.In this work, a series of new nonsteroidal and achiral 17β-HSD2 inhibitors, namely N-benzyl-diphenyl-3(or 4)-carboxamide and N-benzyl-5-phenyl-thiophene-2-carboxamide was designed and the compounds were synthesized in a two to three steps reaction. A small library was built applying parallel synthesis. Highly potent 17β-HSD2 inhibitors could be identified in the thiophene-2-carboxamide class with IC50 in the low nanomolar range. These compounds also showed a good selectivity profile toward 17β-HSD1 and toward the estrogen receptors α and β. The most interesting 17β-HSD2 inhibitor identified in this study is the 5-(2-fluoro-3-methoxyphenyl)-N-(3-hydroxybenzyl)-N-methylthiophene-2-carboxamide 6w displaying an IC50 of 61 nM and a selectivity factor of 73 toward 17β-HSD1.

Graphical abstractA series of new nonsteroidal and achiral 17β-HSD2 inhibitors was designed and synthesized. Highly potent and selective inhibitors could be identified, the most interesting one being 6w.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New class of potent, nonsteroidal and achiral 17β-HSD2 inhibitors discovered. ► N-benzyl-5-phenyl-thiophene-2-carboxamide: best class. ► Good selectivity profile toward 17β-HSD1 and the estrogen receptors. ► Most promising compound: 6w IC50 of 61 nM, SF (17β-HSD1): 73.