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

ABSTRACT: 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 ?-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.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5601374 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Zhang Xuqing X Cai Chaozhong C Sui Zhihua Z Macielag Mark M Wang Yuanping Y Yan Wen W Suckow Arthur A Hua Hong H Bell Austin A Haug Peter P Clapper Wilma W Jenkinson Celia C Gunnet Joseph J Leonard James J Murray William V WV

ACS medicinal chemistry letters 20170727 9

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 β-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 ...[more]

PMID: 28947942

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