Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1): an emerging target for type 2 diabetes

Expert Opin Ther Pat. 2009 Feb;19(2):237-64. doi: 10.1517/13543770802665717.


Background: The family of G-protein-coupled receptors (GPCRs) serves as the target for almost a third of currently marketed drugs and provides the predominant mechanism through which extracellular factors transmit signals to the cell. GPCRs have been proved to be good therapeutic targets for metabolic disorders. In recent years, a number of companies have been actively involved in the discovery of small-molecule modulators of the GPR40 (FFA1) receptor. However, to date, no critical, comprehensive review on small-molecule modulators of GPR40 (FFA1) has been published.

Objective: To review the discovery and development of small-molecule GPR40 (FFA1) agonists/antagonists by different research groups and to classify them based on the key structural features.

Method: Systematic search, analysis, and summary of the publication and patent literature for small-molecule modulators of the GPR40 (FFA1) receptor to June 2008. The patent information for this review is drawn from the Integrity Prous, Scifinder, Esp@cenet, and databases.

Conclusion: The para-substituted phenyl propionic acid scaffold has emerged as a common structural motif found in many GPR40 (FFA1) agonists, and compounds having an aromatic ring and a group capable of releasing a cation have exhibited excellent GPR40 (FFA1) agonistic activity. Several small-molecule agonists of GPR40 (FFA1) have been discovered, which offer a great promise in the treatment of type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Delivery Systems
  • Drug Design
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Patents as Topic
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Structure-Activity Relationship


  • FFAR1 protein, human
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled