Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site

J Med Chem. 2004 Jul 1;47(14):3537-45. doi: 10.1021/jm031121n.


Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.

MeSH terms

  • Adenosine Monophosphate / metabolism
  • Allosteric Site
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cells, Cultured
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glucose / metabolism
  • Glycogen Phosphorylase / antagonists & inhibitors*
  • Glycogen Phosphorylase / chemistry
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Male
  • Models, Molecular
  • Phthalic Acids / chemical synthesis*
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology
  • Protein Binding
  • Rats
  • Rats, Wistar


  • 4-(2,4-bis-(3-nitrobenzoylamino)phenoxy)phthalic acid
  • 4-(2-(3-nitrobenzoylamino)phenoxy)phthalic acid
  • Benzamides
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Phthalic Acids
  • Adenosine Monophosphate
  • Glycogen Phosphorylase
  • Glucose