The free fatty acid receptor 1 (FFA1/GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have been widely considered as promising targets for type 2 diabetes mellitus (T2DM) due to their respective roles in promoting insulin secretion and improving insulin sensitivity. Hence, the dual FFA1/PPARδ agonists may exert synergistic effects by simultaneously activating FFA1 and PPARδ. The present study performed systematic exploration around previously reported FFA1 agonist 2-(2-fluoro-4-((2′-methyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (lead compound), leading to the identification of a novel dual FFA1/PPARδ agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic acid (the optimal compound), which displayed high selectivity over PPARα and PPARγ. In addition, the docking study provided us with detailed binding modes of the optimal compound in FFA1 and PPARδ. Furthermore, the optimal compound exhibited greater glucose-lowering effects than lead compound, which might attribute to its synergistic effects by simultaneously modulating insulin secretion and resistance. Moreover, the optimal compound has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg Therefore, our results provided a novel dual FFA1/PPARδ agonist with excellent glucose-lowering effects in vivo.

游离脂肪酸受体 1 (FFA1/GPR40) 和过氧化物酶体增殖物激活受体 δ (PPARδ) 因其各自在促进胰岛素分泌和改善胰岛素敏感性方面的作用而被广泛认为是 2 型糖尿病 (T2DM) 的有希望的靶点。因此，双 FFA1/PPARδ 激动剂可能通过同时激活 FFA1 和 PPARδ 发挥协同作用。本研究围绕先前报道的 FFA1 激动剂 2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-) 进行了系统探索。 yl）甲氧基）苯氧基）乙酸（先导化合物），从而鉴定出一种新型双 FFA1/PPARδ 激动剂 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy) )苯氧基)乙酸（最佳化合物），对 PPARα 和 PPARγ 表现出高选择性。此外，对接研究为我们提供了 FFA1 和 PPARδ 中最佳化合物的详细结合模式。此外，最佳化合物比先导化合物表现出更大的降糖作用，这可能归因于其通过同时调节胰岛素分泌和抵抗的协同作用。此外，该最佳化合物在 500 mg/kg 高剂量的急性毒性研究中具有可接受的安全性。因此，我们的结果提供了一种新型的双 FFA1/PPARδ 激动剂，具有优异的降糖作用在体内。