title: Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis.
abstract: E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyses the conversion between active 17β-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17β-HSD2 inhibitor may provide a new approach in the onset of osteoporosis. Bicyclic substituted hydroxyphenylmethanone derivatives were synthesised as steroidomimetics of the substrate E2 and were evaluated for their 17β-HSD2 inhibition and their selectivity toward 17β-HSD1, catalysing the reverse reaction the conversion of estrone (E1) into E2. Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC(50) value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17β-HSD1. These results make compound 12 an interesting candidate for further biological evaluation.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Wetzel
authors.forename: Emanuele M
authors.initials: EM
authors.lastname: Gargano
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinsberger
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010024:Osteoporosis / Q000188:drug therapy*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors
chemical_list: D001577:Benzophenones; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human