Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties

J Med Chem. 2012 Jul 26;55(14):6624-8. doi: 10.1021/jm3002026. Epub 2012 Jul 13.


FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Benzene / chemistry
  • Benzene / metabolism
  • Benzene / pharmacokinetics*
  • Benzene / pharmacology*
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship


  • FFAR1 protein, human
  • Receptors, G-Protein-Coupled
  • Benzene