title: New inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
abstract: The estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) is mainly responsible for the conversion of estrone (E1) to the potent estrogen estradiol (E2). It is a key player to control tissue levels of E2 and is therefore an attractive target in estradiol-dependent diseases like breast cancer or endometriosis. We selected a unique non-steroidal pyrimidinone core to start a lead optimization program. We optimized this core by modulation of R1-R6. Its binding mode at the substrate-binding site of 17betaHSD1 is complex and difficult to predict. Nevertheless, some basic structure-activity relationships could be identified. In vitro, the most active pyrimidinone derivative showed effective inhibition of recombinant human 17betaHSD1 at nanomolar concentrations. In intact cells overexpressing the human enzyme, IC50 values in the lower micromolar range were determined. Furthermore, the pyrimidinone proved its use in vivo by significantly reducing 17betaHSD1-dependent tumor growth in a new nude mouse model.
authors.affiliation: Solvay Pharmaceuticals Research Laboratories, Hannover, Germany. josef.messinger@solvay.com
authors.forename: Josef
authors.initials: J
authors.lastname: Messinger
authors.forename: Leena
authors.initials: L
authors.lastname: Hirvelä
authors.forename: Bettina
authors.initials: B
authors.lastname: Husen
authors.forename: Lauri
authors.initials: L
authors.lastname: Kangas
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Olli
authors.initials: O
authors.lastname: Pentikäinen
authors.forename: Pauli
authors.initials: P
authors.lastname: Saarenketo
authors.forename: Hubert
authors.initials: H
authors.lastname: Thole
mesh_terms: D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011487:Protein Conformation; D011744:Pyrimidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D004960:Estradiol Dehydrogenases