Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist

被引：7

作者：

Agarwal, Sameer ^{[1
]}

Sasane, Santosh ^{[1
]}

Deshmukh, Prashant ^{[1
]}

Rami, Bhadresh ^{[1
]}

Bandyopadhyay, Debdutta ^{[1
]}

Giri, Poonam ^{[1
]}

Giri, Suresh ^{[1
]}

Jain, Mukul ^{[1
]}

Desai, Ranjit C. ^{[1
]}

机构：

[1] Cadila Healthcare Ltd, Zydus Res Ctr, Sarkhej Bavla NH 8 A, Ahmadabad 382210, Gujarat, India

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 12期

关键词：

GPR40; agonist; FFAR1; fatty acids; insulin secretion; type; 2; diabetes; BIOAVAILABLE GPR40 AGONIST; TYPE-2; DIABETES-MELLITUS; INSULIN-SECRETION; DOUBLE-BLIND; DISCOVERY; POTENT; TAK-875; TARGETS; SAFETY;

D O I：

10.1021/acsmedchemlett.6b00331

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1134 / 1138

页数：5

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