Design, synthesis and structure–activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker

Abstract The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (−23.7%) at the dose of 50 mg/kg, proximity to the hypoglycemic effect (−27.8%) of Metformin (200 mg/kg). In addition, the compound 17 (100 mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC 0–2 h in type 2 diabetic mice. All of these results indicated that compound 17 was considered to be a promising lead structure suitable for further optimization.