title: Synthesis and biological evaluation of phenyl substituted 1H-1,2,4-triazoles as non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2.
abstract: A series of disubstituted-1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) - a novel and attractive target for the treatment of osteoporosis. 17βHSD2 catalyzes the oxidation of the highly active estrogen 17β-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 17βHSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17βHSD2 inhibitory activity and a good selectivity toward 17βHSD1. They could be a useful tool to map the unexplored enzyme active site.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Saarland, Germany.
authors.forename: Yaseen A
authors.initials: YA
authors.lastname: Al-Soud
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; C045575:1,2,4-triazole; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human