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

• Published in: Bioorganic & medicinal chemistry 2017-04, Vol.25 (8), p.2445-2450
• Main Authors: Yang, Jianyong, Li, Zheng, Li, Huilan, Liu, Chunxia, Wang, Nasi, Shi, Wei, Liao, Chen, Cai, Xingguang, Huang, Wenlong, Qian, Hai
• Format: Article
• Language: English
• Subjects: Amide; Amides - chemistry; Animals; Area Under Curve; Blood Glucose - analysis; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - drug therapy; Fatty Acids, Nonesterified - agonists; FFA1 agonist; Glucose Tolerance Test; GPR40; Hybrid; Mice; Structure-Activity Relationship; Type 2 diabetes
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.03.001

[Display omitted] 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 50mg/kg, proximity to the hypoglycemic effect (−27.8%) of Metformin (200mg/kg). In addition, the compound 17 (100mg/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.