Synthesis and biological evaluation of phenyl substituted 1H-1,2,4-triazoles as non-steroidal inhibitors of 17ß-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 17ß-hydroxysteroid dehydrogenase type 2 (17ßHSD2) - a novel and attractive target for the treatment of osteoporosis. 17ßHSD2 catalyzes the oxidation of the highly active estrogen 17ß-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 17ßHSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17ßHSD2 inhibitory activity and a good selectivity toward 17ßHSD1. They could be a useful tool to map the unexplored enzyme active site.