Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist

Bioorg Med Chem Lett. 2017 Mar 1;27(5):1278-1283. doi: 10.1016/j.bmcl.2017.01.034. Epub 2017 Jan 17.

Abstract

The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.

Keywords: Free fatty acid receptor 1; Free fatty acid receptor 4; GPR120; Phenylpropanoic acid; Type 2 diabetes.

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / pharmacology*
  • Phenylpropionates / therapeutic use
  • Protein Binding / drug effects
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • FFAR4 protein, mouse
  • Phenylpropionates
  • Receptors, G-Protein-Coupled