title: Introduction of an electron withdrawing group on the hydroxyphenylnaphthol scaffold improves the potency of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors.
abstract: Estrogen deficiency in postmenopausal women or elderly men is often associated with the skeletal disease osteoporosis. The supplementation of estradiol (E2) in osteoporotic patients is known to prevent bone fracture but cannot be administered because of adverse effect. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) oxidizes E2 to its inactive form estrone (E1) and has been found in osteoblastic cells, it is an attractive target for the treatment of osteoporosis. Twenty-one novel, naphthalene-derived compounds have been synthesized and evaluated for their 17β-HSD2 inhibition and their selectivity toward 17β-HSD1 and the estrogen receptors (ERs) α and β. Compound 19 turned out to be the most potent and selective inhibitor of 17β-HSD2 in cell-free assays and had a very good cellular activity in MDA-MB-231 cells, expressing naturally 17β-HSD2. It also showed marked inhibition of the E1-formation by the rat and mouse orthologous enzymes and strong inhibition of monkey 17β-HSD2. It is thus an appropriate candidate to be further evaluated in a disease-oriented model.
authors.affiliation: Saarland University, Saarbrücken, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Wetzel
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases; D000818:Animals; D001667:Binding, Competitive; D002144:Callithrix; D045744:Cell Line, Tumor; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C569669:6-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-naphthol; D009284:Naphthols; D010636:Phenols; D011960:Receptors, Estrogen; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)); D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human