title: Bicyclic substituted hydroxyphenylmethanone type inhibitors of 17 β-hydroxysteroid dehydrogenase Type 1 (17 β-HSD1): the role of the bicyclic moiety.
abstract: 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): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-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 17β-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 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 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 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, & the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2 3, P.O. Box 151150, 66123 Saarbrücken, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Oster
authors.forename: Tobias
authors.initials: T
authors.lastname: Klein
authors.forename: Claudia
authors.initials: C
authors.lastname: Henn
authors.forename: Ruth
authors.initials: R
authors.lastname: Werth
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human