title: Novel estrone mimetics with high 17beta-HSD1 inhibitory activity.
abstract: 17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of estrone into estradiol, which is the most potent estrogen in humans. Lowering intracellular estradiol concentration by inhibition of this enzyme is a promising new option for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Combination of ligand- and structure-based design resulted in heterocyclic substituted biphenylols and their aza-analogs as new 17beta-HSD1 inhibitors. The design was based on mimicking estrone, especially focusing on the imitation of the D-ring keto group with (substituted) heterocycles. Molecular docking provided insights into plausible protein-ligand interactions for this class of compounds. The most promising compound 12 showed an inhibitory activity in the high nanomolar range and very low affinity for the estrogen receptors alpha and beta. Thus, compound 12 is a novel tool for the elucidation of the pharmacological relevance of 17beta-HSD1 and might be a lead for the treatment of estrogen-dependent diseases.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Oster
authors.forename: Tobias
authors.initials: T
authors.lastname: Klein
authors.forename: Ruth
authors.initials: R
authors.lastname: Werth
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruchten
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bey
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
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: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D032701:Biomimetics / Q000379:methods; D001943:Breast Neoplasms; D003198:Computer Simulation; D015195:Drug Design; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase