We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure–activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC₅₀ values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

中文翻译：

---

发现基于异噻唑的苯基丙酸GPR120激动剂作为2型糖尿病的发展候选者

我们发现了一系列新的基于异噻唑的苯基丙酸作为GPR120激动剂。广泛的结构-活性关系研究导致发现强效的GPR120激动剂4x，在钙和β-arrestin分析中均显示出良好的EC ₅₀值。它还具有良好的药物特性和良好的PK曲线。此外，它在C57BL / 6 DIO小鼠中表现出体内抗糖尿病活性。WT和基因敲除DIO小鼠的研究表明，它通过GPR120改善了OGTT期间的葡萄糖处理。总体而言，4x具有抗糖尿病作用和良好的安全性，有望成为开发候选药物。