The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC₅₀ = 7.9 nM), which exhibited improved lipophilicity (LogD_7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.

由于游离脂肪酸受体1（FFA1）在扩大胰岛素分泌中的作用，因此被认为是一种新型的抗糖尿病靶标。我们以前已经确定了具有不同杂环支架的几个FFA1激动剂系列。在这里，我们描述了由药物样理化性质指导的其他杂环支架的结构探索。进一步的基于结构的设计和手性拆分提供了最有效的化合物11（EC ₅₀  = 7.9 nM），表现出改进的亲脂性（LogD _7.4：1.93），配体效率（LE = 0.32）和配体亲脂性效率（LLE = 6.2）。此外，化合物11在血浆清除率，最大浓度和血浆暴露方面，它显示出比TAK-875更好的药代动力学性质。尽管化合物11具有强大的激动活性和PK曲线，但体内降低葡萄糖的作用并不理想，而且体内/体外差异的确切原因值得进一步探讨。