title: Estrone C15 derivatives--a new class of 17beta-hydroxysteroid dehydrogenase type 1 inhibitors.
abstract: Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has been proposed as a promising new therapeutic option to treat estrogen-dependent diseases like endometriosis and breast cancer. Based on a molecular modelling approach we designed and synthesized novel C15-substituted estrone derivatives. Subsequent biological evaluation revealed that potent inhibitors of human 17beta-HSD1 can be identified in this compound class. The best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10nM and had no effect on the activity of recombinant human 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol inactivation. These properties were retained in a cell-based enzyme activity assays. In spite of the estrogen backbone compound 21 did not show estrogen receptor mediated effects in vitro or in vivo. In conclusion, estrone C15 derivative compound 21 can be regarded as a promising lead compound for further development as a 17beta-HSD1 inhibitor.
authors.affiliation: Solvay Pharmaceuticals Research Laboratories, Hans-Böckler-Allee 20, D-30173 Hannover, Germany. josef.messinger@solvay.com
authors.forename: Josef
authors.initials: J
authors.lastname: Messinger
authors.forename: Bettina
authors.initials: B
authors.lastname: Husen
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Leena
authors.initials: L
authors.lastname: Hirvelä
authors.forename: Lila
authors.initials: L
authors.lastname: Kallio
authors.forename: Pauli
authors.initials: P
authors.lastname: Saarenketo
authors.forename: Hubert
authors.initials: H
authors.lastname: Thole
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000737:chemistry; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D004970:Estrone; D004958:Estradiol; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; C523763:HSD17B2 protein, human