Bioorganic and Medicinal Chemistry p. 2445 - 2450 (2017)
Update date:2022-07-30
Topics:
Yang, Jianyong
Li, Zheng
Li, Huilan
Liu, Chunxia
Wang, Nasi
Shi, Wei
Liao, Chen
Cai, Xingguang
Huang, Wenlong
Qian, Hai
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 AUC0–2?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.
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