Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were designed and synthesized, featuring OC and SO2-N linkage. For the OC linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC₅₀ of 5.81 ± 0.04 and exhibited at least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC₅₀ of 5.66 ± 0.04 and displayed>46-fold selectivity against FFA1. Among these two series of compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1, demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was better than a clinical phase III drug TAK875. This study provides guidance for FFA4 ligand design and drug optimization.

游离脂肪酸受体4（FFA4）已被认为是代谢性疾病的诱人靶标。为了找到有效和选择性的FFA4激动剂，设计并合成了具有O C和SO2-N键的28种3-（4-（苯氧基甲基）苯基）丙酸和N-苯基苯磺酰胺衍生物。对于O C键化合物，1g的FFA4激动作用最强，pEC ₅₀为5.81±0.04，对FFA1的选择性至少为64倍。对于SO2-N键合激动剂，2m的pEC ₅₀为5.66±0.04，对FFA1的选择性> 46倍。在这两个系列的化合物中，1g对接模拟显示，它是FFA4最有效的激动剂和对FFA1的最佳选择性。此外，1g对其他七个GPCR表现出受体选择性。在抗糖尿病评估中，1g剂量依赖性地降低了血糖，优于临床III期药物TAK875。这项研究为FFA4配体设计和药物优化提供了指导。