Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes

被引：23

作者：

Zhang, Xuqing ^{[1
]}

Cai, Chaozhong ^{[1
]}

Sui, Zhihua ^{[1
]}

Macielag, Mark ^{[1
]}

Wang, Yuanping ^{[1
]}

Yan, Wen ^{[1
]}

Suckow, Arthur ^{[1
]}

Hua, Hong ^{[1
]}

Bell, Austin ^{[1
]}

Haug, Peter ^{[1
]}

Clapper, Wilma ^{[1
]}

Jenkinson, Celia ^{[1
]}

Gunnet, Joseph ^{[1
]}

Leonard, James ^{[1
]}

Murray, William V. ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Cardiovasc & Metab Res, Welsh & McKean Rd,Box 776, Spring House, PA 19477 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 09期

关键词：

GPR120; phenylpropanoic acid; type; 2; diabetes; RECEPTOR; 4; FFA4/GPR120; INSULIN-RESISTANCE; FATTY-ACIDS; POTENT; IDENTIFICATION; RODENTS; DESIGN; MICE;

D O I：

10.1021/acsmedchemlett.7b00233

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and beta-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

引用

页码：947 / 952

页数：6

共 39 条

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