PPARα x PPARγ x GPR40 x PPARδ

更新于：2024-11-01

基本信息

关联

项与 PPARα x PPARγ x GPR40 x PPARδ 相关的药物

ZLY18

靶点

GPR40 x PPARα x PPARγ x PPARδ

作用机制

GPR40激动剂 [+3]

在研机构

广东药科大学

原研机构

广东药科大学

在研适应症

非酒精性脂肪性肝炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PPARα x PPARγ x GPR40 x PPARδ 相关的临床结果

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100 项与 PPARα x PPARγ x GPR40 x PPARδ 相关的转化医学

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0 项与 PPARα x PPARγ x GPR40 x PPARδ 相关的专利（医药）

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项与 PPARα x PPARγ x GPR40 x PPARδ 相关的文献（医药）

2022-02-01·Bioorganic & Medicinal Chemistry3区 · 医学

Design, synthesis, and biological evaluation of novel dual FFA1 and PPARδ agonists possessing phenoxyacetic acid scaffold

3区 · 医学

Article

作者: He, Yepu ; Cai, Zongyu ; Yang, Benhui ; Zhou, Zongtao ; Chen, Lianru ; Zhang, Congzi ; Li, Zheng ; Zhang, Luyong

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.

2019-11-01·Bioorganic Chemistry2区 · 化学

Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPARδ agonists as potential anti-diabetic agents

2区 · 化学

Article

作者: Li, Zheng ; Hu, Lijun ; Deng, Liming ; Zhou, Zongtao ; Wang, Xuekun ; 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 compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted 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 compound 19.