Potent and Selective Steroidal Inhibitors of 17β-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.7488-7502
• Main Authors: Bellavance, Édith, Luu-The, Van, Poirier, Donald
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Medical sciences; Miscellaneous; Oxidoreductases; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900921c

17β-Hydroxysteroid dehydrogenase type 7 (17β-HSD7) catalyzes the reduction of estrone (E1) into estradiol (E2) and of dihydrotestosterone (DHT) into 5α-androstane-3β,17β-diol (3β-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5α-androstane derivatives differing in their C-17 substituent: 17β-formamide, 17β-benzamide, and 17β-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E1 into E2 (IC50 = 189−451 nM) and also toward the conversion of DHT into 3β-diol (69−91% at 3 μM). Inhibition assays with 17β-HSD1, 17β-HSD5, 5α-reductase (5α-R) 1 and 5α-R2 revealed that 17β-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5α-Rs but not the other enzymes tested. Two 4-aza-5α-androstane inhibitors were, however, selective and still showed good inhibition of 17β-HSD7. First selective and efficient inhibitors of 17β-HSD7 are now available for additional mechanistic and therapeutic studies.