Design, Synthesis and Structure−Activity Relationship Studies of Novel Free Fatty Acid Receptor 1 Agonists Bearing Amide Linker

Publication date: Available online 2 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jianyong Yang, Zheng Li, Huilan Li, Chunxia Liu, Nasi Wang, Wei Shi, Chen Liao, Xingguang Cai, Wenlong Huang, Hai Qian
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 AUC0-2h 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.

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