Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors

Bioorg Med Chem. 2008 Sep 15;16(18):8627-34. doi: 10.1016/j.bmc.2008.08.010. Epub 2008 Aug 7.

Abstract

During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2'E)-N,N'-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC(50) value of 0.023 microM. An X-ray crystallographic study of the enzyme-6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.

Publication types

  • Evaluation Study

MeSH terms

  • Acrylamides / chemical synthesis
  • Acrylamides / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Dichlorophen / chemical synthesis
  • Dichlorophen / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Phosphorylase, Liver Form / antagonists & inhibitors*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacology*
  • Solvents / chemistry
  • Structure-Activity Relationship

Substances

  • Acrylamides
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Solvents
  • Glycogen Phosphorylase, Liver Form
  • Dichlorophen