Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide Derivatives as Inhibitors of Human Liver Glycogen Phosphorylase A

Bioorg Med Chem. 2008 May 15;16(10):5452-64. doi: 10.1016/j.bmc.2008.04.010. Epub 2008 Apr 11.

Abstract

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Diabetes Mellitus, Experimental / drug therapy
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Phosphorylase, Liver Form / antagonists & inhibitors*
  • Glycogen Phosphorylase, Liver Form / chemistry
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / therapeutic use
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Liver / enzymology*
  • Mice
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Stereoisomerism

Substances

  • 5-chloro-N-(4-(1,2-dihydroxyethyl)phenyl)-1H-indole-2-carboxamide
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Indoles
  • Glycogen Phosphorylase, Liver Form

Associated data

  • PDB/1EXV
  • PDB/2ZB2