Synthesis, Activity, and Docking Study of Novel Phenylthiazole‐Carboxamido Acid Derivatives as FFA2 Agonists

Free fatty acid receptor 2 ( FFA 2), also known as GPR 43, is activated by short‐chain fatty acids ( SCFA s) that are mainly produced by the gut microbiota through the fermentation of undigested carbohydrates and dietary fibers. FFA 2 currently appears to be a potential target in the management of obesity, diabetes, inflammatory diseases, and cancer. In the study, a series of novel phenylthiazole‐carboxamido acid derivatives has been synthesized and evaluated as potential orthosteric FFA 2 ligands for the study of structure–activity relationships. Compound 6e was found to exhibit the twofold potent agonistic activity in the stable hFFA 2‐transfected CHO ‐K1 cells ( EC 50 = 23.1 μ m ) as that of positive control propionate ( EC 50 = 43.3 μ m ). We also reported the results of mutagenesis studies based on the crystal structure of hFFA 1 bound to TAK ‐875 at 2.3 Å resolution to identify important residues for orthosteric agonist 6e inducing FFA 2 activation.