title: Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Oncology and Molecular Endocrinology, CHUQ (CHUL) Research Center and Laval University, 2705 Boulevard Laurier, Québec G1V 4G2, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Bellavance
authors.forename: Van
authors.initials: V
authors.lastname: Luu-The
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000378:metabolism; D000731:Androstanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055162:Biocatalysis; D002460:Cell Line; D013196:Dihydrotestosterone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D004970:Estrone / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D010084:Oxidation-Reduction; D013379:Substrate Specificity
chemical_list: D000731:Androstanes; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; C033936:androstane