Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): The Role of the Bicyclic Moiety

An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17 beta-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17 beta-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17 beta-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17 beta HSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nm (cell-free assay) and 78 nm (cellular assay), high selectivity for 17 beta-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17 beta-HSD1.