Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11β-HSD1 inhibitors: potential impact in diabetes

Eur J Med Chem. 2013 Jul:65:403-14. doi: 10.1016/j.ejmech.2013.05.010. Epub 2013 May 18.

Abstract

The biological screening of a collection of nature occurring diterpenoids against 11β-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11β-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11β-HSD1) = 9.4 nM and selectivity index (human 11β-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11β-HSD1 were generated using docking simulations. Based on the results, the structural-activity relationships (SARs) of compounds 1b and 2 were also discussed.

Keywords: Diabetes; Selective 11β-HSD1 inhibitors; Structure–activity relationship studies; Urea derivatives; ent-Kaurene diterpenoids.

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
  • Animals
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Structure-Activity Relationship

Substances

  • Diterpenes
  • Enzyme Inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1