Introduction of an electron withdrawing group on the hydroxyphenylnaphthol scaffold improves the potency of 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibitors.
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Wetzel M, Marchais-Oberwinkler S, Perspicace E, Moller G, Adamski J, Hartmann RW
Introduction of an electron withdrawing group on the hydroxyphenylnaphthol scaffold improves the potency of 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibitors.
J Med Chem. 2011 Nov 10;54(21):7547-57. doi: 10.1021/jm2008453. Epub 2011 Oct 19.
- PubMed ID
- 21972996 [ View in PubMed]
- 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 17beta-hydroxysteroid dehydrogenase type 2 (17beta-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 17beta-HSD2 inhibition and their selectivity toward 17beta-HSD1 and the estrogen receptors (ERs) alpha and beta. Compound 19 turned out to be the most potent and selective inhibitor of 17beta-HSD2 in cell-free assays and had a very good cellular activity in MDA-MB-231 cells, expressing naturally 17beta-HSD2. It also showed marked inhibition of the E1-formation by the rat and mouse orthologous enzymes and strong inhibition of monkey 17beta-HSD2. It is thus an appropriate candidate to be further evaluated in a disease-oriented model.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Estradiol acetate Estradiol 17-beta-dehydrogenase 2 Protein Humans UnknownNot Available Details Estradiol benzoate Estradiol 17-beta-dehydrogenase 2 Protein Humans UnknownNot Available Details Estradiol cypionate Estradiol 17-beta-dehydrogenase 2 Protein Humans UnknownNot Available Details Estradiol dienanthate Estradiol 17-beta-dehydrogenase 2 Protein Humans UnknownNot Available Details Estradiol valerate Estradiol 17-beta-dehydrogenase 2 Protein Humans UnknownNot Available Details