Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis
| Autor: | Stefan Hinsberger, Rolf W. Hartmann, Emanuele M. Gargano, Marie Wetzel, Sandrine Marchais-Oberwinkler |
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| Rok vydání: | 2012 |
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Molecular Pharmacology Bicyclic molecule Stereochemistry Drug discovery Organic Chemistry Molecular Conformation Substrate (chemistry) Dehydrogenase Estrone General Medicine Estradiol Dehydrogenases Benzophenones Inhibitory Concentration 50 chemistry.chemical_compound Receptors Estrogen chemistry Drug Discovery Osteoporosis Enzyme Inhibitors Hydroxysteroid dehydrogenase Selectivity IC50 hormones hormone substitutes and hormone antagonists |
| Zdroj: | European Journal of Medicinal Chemistry. 47:1-17 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2011.09.004 |
| Popis: | 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 IC50 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. |
| Databáze: | OpenAIRE |
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