The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators

Bioorg Med Chem Lett. 2010 Jan 15;20(2):493-8. doi: 10.1016/j.bmcl.2009.11.112. Epub 2009 Nov 26.


Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / pharmacokinetics
  • Allosteric Regulation
  • Animals
  • Cyclic AMP / metabolism
  • Drug Discovery
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats
  • Receptors, Cell Surface / agonists*
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship


  • Acetamides
  • FFA2R protein, human
  • Ffar2 protein, mouse
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Cyclic AMP