tug-469 and Diabetes-Mellitus--Type-2

GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

Topics: Biphenyl Compounds; Cell Survival; Cinnamates; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; HEK293 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Phenylpropionates; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

Topics: Animals; Cell Line, Tumor; Cell Membrane Permeability; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin Secretion; Microsomes, Liver; Models, Molecular; Phenylpropionates; Pyridines; Rats; Receptors, G-Protein-Coupled; Recombinant Proteins; Structure-Activity Relationship