Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-propionic acid as a novel series of G protein-coupled receptor 40 agonists

J Med Chem. 2007 Jun 14;50(12):2807-17. doi: 10.1021/jm070130j. Epub 2007 May 15.


High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.

MeSH terms

  • Animals
  • Biological Availability
  • Calcium / metabolism
  • Cell Line
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / pharmacology
  • Propionates / chemical synthesis*
  • Propionates / pharmacokinetics
  • Propionates / pharmacology
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship


  • 3-(4-(methylbutoxy)phenyl)-3-phenylpropionic acid
  • FFAR1 protein, human
  • Hypoglycemic Agents
  • Insulin
  • Phenylpropionates
  • Propionates
  • Receptors, G-Protein-Coupled
  • Calcium