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Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11?-hydroxysteroid dehydrogenase 2 inhibitors

Gaware, Rawindra and Khunt, Rupesh and Czollner, Laszlo and Stanetty, Christian and Da Cunha, Thierry and Kratschmar, Denise V. and Odermatt, Alex and Kosma, Paul and Jordis, Ulrich and Classen-Houben, Dirk. (2011) Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11?-hydroxysteroid dehydrogenase 2 inhibitors. Bioorganic & medicinal chemistry, Vol. 19, H. 6. pp. 1866-1880.

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Official URL: http://edoc.unibas.ch/dok/A6001601

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Abstract

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11?-hydroxysteroid dehydrogenase (11?-HSD) type 1 and type 2. Whereas inhibition of 11?-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11?-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11?-HSD2. The most potent and selective compound is active against human 11?-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11?-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11?-HSD1 and 11?-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11?-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Kratschmar, Denise and Da Cunha, Thierry
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0968-0896
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:11 Oct 2012 15:31
Deposited On:11 Oct 2012 15:18

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