Discovery of novel orally bioavailable GPR40 agonists

Bioorg Med Chem Lett. 2013 May 15;23(10):2920-4. doi: 10.1016/j.bmcl.2013.03.060. Epub 2013 Mar 26.

Abstract

The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzofurans / administration & dosage
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Macaca mulatta
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Sulfones / administration & dosage
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • Benzofurans
  • FFAR1 protein, human
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • Sulfones
  • TAK-875