Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist
Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist
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DOI：
10.1021/acsmedchemlett.6b00331
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发表时间：
2016-12-01
影响因子：
4.2
通讯作者：
Desai, Ranjit C.
中科院分区：
文献类型：
--
作者：
Agarwal, Sameer;Sasane, Santosh;Desai, Ranjit C.
GPR40/FFARI是一种G蛋白偶联受体，主要在胰岛β细胞中表达，并被长链游离脂肪酸激活，介导葡萄糖刺激的胰岛素分泌增加。合成了一系列新的取代3-(4-芳氧基芳基)丙酸衍生物，并对它们作为GPR40激动剂的活性进行了评价，从而鉴定了化合物5，该化合物在体外具有很高的活性，在nSTZ Wistar大鼠糖尿病模型(ED50=0.8 mg/kg；ED90=3.1 mg/kg)的口服葡萄糖耐量试验中表现出较强的降糖作用，具有良好的药代动力学特征，且不具有细胞色素P450异构体抑制活性。
GPR40/FFARI is a G protein-coupled receptor predominantly expressed in pancreatic beta-cells and activated by long-chain free fatty acids, mediating enhancement of glucose stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity.