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

Bioorg Med Chem. 2010 Nov 1;18(21):7522-41. doi: 10.1016/j.bmc.2010.08.046. Epub 2010 Sep 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
  • Animals
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / chemical synthesis
  • Glycyrrhetinic Acid / pharmacology
  • Humans
  • Hydroxamic Acids / chemistry*
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Glycyrrhetinic Acid