Identification of pentacyclic triterpenes derivatives as potent inhibitors against glycogen phosphorylase based on 3D-QSAR studies

Eur J Med Chem. 2011 Jun;46(6):2011-21. doi: 10.1016/j.ejmech.2011.02.053. Epub 2011 Feb 27.

Abstract

Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure-activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1 μM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Phosphorylase, Muscle Form / antagonists & inhibitors*
  • Glycogen Phosphorylase, Muscle Form / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Muscle, Skeletal / enzymology
  • Pentacyclic Triterpenes / chemical synthesis
  • Pentacyclic Triterpenes / chemistry
  • Pentacyclic Triterpenes / pharmacology*
  • Quantitative Structure-Activity Relationship*
  • Rabbits
  • Stereoisomerism

Substances

  • Enzyme Inhibitors
  • Pentacyclic Triterpenes
  • Glycogen Phosphorylase, Muscle Form