Synthesis and Biological Evaluation of Phenyl Substituted 1H-1,2,4-Triazoles as Non-Steroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2

A series of disubstituted-1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17 beta-hydroxysteroid dehydrogenase type 2 (17 beta HSD2) a novel and attractive target for the treatment of osteoporosis. 17 beta HSD2 catalyzes the oxidation of the highly active estrogen 17 beta-estradiol (E2) and androgen testosterone (T) into the weak estrone and androstenedione, respectively. Inhibition of this enzyme will locally in the bone lead to an increase in E2 and T levels, two key players in the maintenance of the balance between bone resorption and bone formation. In this study, a new class of 17 beta HSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17 beta HSD2 inhibitory activity and a good selectivity toward 17 beta HSD1. They could be a useful tool to map the unexplored enzyme active site.