title: Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Natural Resources and Applied Life Sciences, Muthgasse 18, 1190 Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Stanetty
authors.forename: Laszlo
authors.initials: L
authors.lastname: Czollner
authors.forename: Iris
authors.initials: I
authors.lastname: Koller
authors.forename: Priti
authors.initials: P
authors.lastname: Shah
authors.forename: Rawindra
authors.initials: R
authors.lastname: Gaware
authors.forename: Thierry Da
authors.initials: TD
authors.lastname: Cunha
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jordis
authors.forename: Paul
authors.initials: P
authors.lastname: Kosma
authors.forename: Dirk
authors.initials: D
authors.lastname: Classen-Houben
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid