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

• Published in: Archiv der Pharmazie (Weinheim) Vol. 345; no. 8; pp. 610 - 621
• Main Authors: Al-Soud, Yaseen A., Marchais-Oberwinkler, Sandrine, Frotscher, Martin, Hartmann, Rolf W.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.08.2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 17βHSD2; 4-triazoles; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Disubstituted 1H-1; Disubstituted 1H‐1,2,4‐triazoles; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Estradiol Dehydrogenases - antagonists & inhibitors; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Molecular Structure; Non-steroidal inhibitor; Osteoporosis; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Steroidomimetics; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; ALDOSTERONE SYNTHASE INHIBITORS; Disubstituted 1H-1; DESIGN; 17 ss HSD2; ESTROGEN-DEPENDENT DISEASES; Osteoporosis; 2; Non-steroidal inhibitor; 4-triazoles; ENZYME; STEROID-5-ALPHA-REDUCTASE TYPE-1; IN-VIVO; Steroidomimetics; 17-BETA-HSD1; HIGHLY POTENT; AROMATASE INHIBITORS; SELECTIVITY
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201200025

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. 17β‐Hydroxysteroid dehydrogenase type 2 (17βHSD2) oxidizes estradiol E2 into estrone. As E2 can induce bone formation acting on the osteoblasts and as 17βHSD2 is expressed in osteoblastic cells, this enzyme is a novel and attractive target for the treatment of osteoporosis. A new class of 17βHSD2 inhibitors with a 1H‐1,2,4‐triazole scaffold was identified. The best compounds show moderate 17βHSD2 inhibition (IC50 between 1.4 and 4 µM) and a good selectivity toward 17βHSD1. They can also be a useful tool to map the unexplored enzyme active site.