Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2949-53. doi: 10.1016/j.bmcl.2014.04.065. Epub 2014 Apr 26.

Abstract

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.

Keywords: Agonist; Diabetes; GPR40; Glucose lowering; Insulin secretagogue.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glucose Tolerance Test
  • Humans
  • Molecular Structure
  • Propionates / administration & dosage
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Rats, Zucker
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • FFAR1 protein, human
  • G-protein-coupled receptor 40, rat
  • Propionates
  • Receptors, G-Protein-Coupled
  • propionic acid