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

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.

• Authors: Steven M Sparks, Christopher Aquino, Pierette Banker, Jon L Collins, David Cowan, Caroline Diaz, Steven T Dock, Donald L Hertzog, Xi Liang, Erin D Swiger, Josephine Yuen, Grace Chen, Channa Jayawickreme, David Moncol, Christopher Nystrom, Vincent Rash, Thomas Rimele, Shane Roller, Sean Ross
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 5 Pg. 1278-1283 (03 01 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28148462 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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