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Kratschmar D.V.,University of Basel | Vuorinen A.,University of Innsbruck | Da Cunha T.,University of Basel | Wolber G.,Free University of Berlin | And 5 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2011

Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18β-Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11β-HSD1 and fifteen 11β-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11β-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11β-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11β-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11β-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11β-HSD1 or 11β-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11β-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. © 2011 Elsevier Ltd. All rights reserved.


Amer H.,University of Natural Resources and Life Sciences, Vienna | Mereiter K.,Vienna University of Technology | Stanetty C.,University of Natural Resources and Life Sciences, Vienna | Hofinger A.,University of Natural Resources and Life Sciences, Vienna | And 6 more authors.
Tetrahedron | Year: 2010

A general method for the introduction of thiol groups at positions 1, 2, and 3 of glycyrrhetinic acid has been developed starting from a protected 2α,3α-oxido-derivative. Conversion into the corresponding 2β,3β-epithio-derivative was followed by ring-opening leading to either 2- or 3-substituted thio derivatives. Conversely, 3α-configured allylic alcohol intermediates derived from the 2,3-epoxide provided efficient access to both diastereoisomeric 3-thio derivatives as well as 1α-thio derivatives. The stereochemistry of the newly formed stereogenic centers was rigorously proven using X-ray crystallography. © 2010 Elsevier Ltd. All rights reserved.


Stanetty C.,University of Natural Resources and Life Sciences, Vienna | Czollner L.,Vienna University of Technology | Koller I.,University of Natural Resources and Life Sciences, Vienna | Shah P.,Vienna University of Technology | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

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. © 2010 Elsevier Ltd. All rights reserved.


Gaware R.,Vienna University of Technology | Khunt R.,Vienna University of Technology | Czollner L.,Vienna University of Technology | Stanetty C.,University of Natural Resources and Life Sciences, Vienna | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

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. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing 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. 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 11β-HSD1 and 11β-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 11β-HSD2 in the lower nanomolar range with up to 3600-fold selectivity. © 2011 Elsevier B.V. All rights reserved.


Patent
Onepharm Research and Development GmbH | Date: 2011-05-11

The present invention relates to the use of an 11--HSD-type 1 and/or type 2 inhibitor for the manufacture of a pharmaceutical agent for the prevention and/or treatment of inflammation-induced and/or immune-mediated loss of bone and/or cartilage.

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