Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPAR delta agonists as potential anti-diabetic agents
Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPAR delta agonists as potential anti-diabetic agents
复制标题
作为潜在抗糖尿病药物的新型双 FFA1 (GPR40)/PPAR δ 激动剂的设计、合成和生物学评价
DOI：
10.1016/j.bioorg.2019.103254
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发表时间：
2019
影响因子：
5.1
通讯作者：
Zhang Luyong
中科院分区：
文献类型：
--
作者：
Li Zheng;Hu Lijun;Wang Xuekun;Zhou Zongtao;Deng Liming;Xu Yawen;Zhang Luyong
The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound19with considerable oral pharmacokinetic profile. Compound19exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound19exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound19.
