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Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Stanetty Christian, Czollner Laszlo, Koller Iris, Shah Priti, Gaware Rawindra, Cunha Thierry Da, Odermatt Alex, Jordis Ulrich, Kosma Paul, Classen-Houben Dirk,
Project The Regulation of Glucocorticoid and Mineralocorticoid Hormone Action by 11beta-Hydroxysteroid Dehydrogenases
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Original article (peer-reviewed)

Journal Bioorganic & medicinal chemistry
Volume (Issue) 18(21)
Page(s) 7522 - 41
Title of proceedings Bioorganic & medicinal chemistry
DOI 10.1016/j.bmc.2010.08.046


Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11β-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11β-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1.