A novel class of antagonists for the FFAs receptor GPR40

Biochem Biophys Res Commun. 2009 Dec 18;390(3):557-63. doi: 10.1016/j.bbrc.2009.10.004. Epub 2009 Oct 8.


The free fatty acid receptor, GPR40, is implicated in the pathophysiology of type 2 diabetes, and is a new potential drug target for the treatment of type 2 diabetes. Its antagonist is thought to be not only a useful chemical probe for further exploring the function of GPR40 but also a lead structure for drug development. With virtual screening based on a homology model followed by a cell-based calcium mobilization assay, we found that sulfonamides are a new class of small organic antagonists for GPR40. One of the compounds, DC260126, dose-dependently inhibited GPR40-mediated Ca(2+) elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid (IC(50): 6.28+/-1.14, 5.96+/-1.12, 7.07+/-1.42, 4.58+/-1.14 microM, respectively), reduced GTP-loading and ERK1/2 phosphorylation stimulated by linoleic acid in GPR40-CHO cells, suppressed palmitic acid potentiated glucose-stimulated insulin secretion, and negatively regulated GPR40 mRNA expression induced by oleic acid in Min6 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cattle
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • Fatty Acids, Nonesterified / antagonists & inhibitors*
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / isolation & purification
  • Hypoglycemic Agents / pharmacology
  • Models, Molecular
  • Protein Conformation
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Sulfonamides / chemistry*
  • Sulfonamides / isolation & purification
  • Sulfonamides / pharmacology


  • DC26012
  • FFAR1 protein, human
  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled
  • Sulfonamides