Design, synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1

作者：Jiaju Yang, Enke Gu, Ting Yan, Daoming Shen, Bainian Feng, Chunlei Tang · 发表于：Chemical Biology & Drug Design · 年份：2019 · DOI：10.1111/cbdd.13480 · 被引用次数：5 · 研究领域：Diabetes Treatment and Management、Pancreatic function and diabetes、Metabolism, Diabetes, and Cancer

Abstract Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK‐875, AMG‐837, and LY2881835. Among them, most promising compounds 7 , 14 , and 15 were obtained with EC 50 values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK‐875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7 , 14 , and 15 had significant glucose‐lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.