Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists

J Med Chem. 2011 Mar 10;54(5):1365-78. doi: 10.1021/jm101405t. Epub 2011 Feb 14.


G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic β-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.

MeSH terms

  • Administration, Oral
  • Animals
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology
  • Blood Glucose / analysis
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy
  • Drug Design
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Male
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship


  • 3-(4-((2',6'-dimethylbiphenyl-3-yl)methoxy)-2-fluorophenyl)propanoic acid
  • Biphenyl Compounds
  • Blood Glucose
  • FFAR1 protein, human
  • Hypoglycemic Agents
  • Phenylpropionates
  • Receptors, G-Protein-Coupled