Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone

• Published in: Journal of medicinal chemistry 2009-12, Vol.52 (23), p.7488
• Main Authors: Bellavance, Edith, Luu-The, Van, Poirier, Donald
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 17-Hydroxysteroid Dehydrogenases - metabolism; Androstane-3,17-diol - metabolism; Androstanes - chemical synthesis; Androstanes - chemistry; Androstanes - pharmacology; Biocatalysis; Cell Line; Dihydrotestosterone - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Estradiol - metabolism; Estrone - metabolism; Humans; Inhibitory Concentration 50; Oxidation-Reduction; Substrate Specificity
• ISSN: 1520-4804
• DOI: 10.1021/jm900921c

17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.