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

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

  • ACS Med Chem Lett. 2017 Jul 27;8(9):947-952. doi: 10.1021/acsmedchemlett.7b00233.
Xuqing Zhang 1,  Chaozhong Cai 1,  Zhihua Sui 1,  Mark Macielag 1,  Yuanping Wang 1,  Wen Yan 1,  Arthur Suckow 1,  Hong Hua 1,  Austin Bell 1,  Peter Haug 1,  Wilma Clapper 1,  Celia Jenkinson 1,  Joseph Gunnet 1,  James Leonard 1,  William V Murray 1
Affiliations

Affiliation

  • 1 Cardiovascular and Metabolic Research, Janssen Research & Development, LLC, Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
PMID: 28947942 DOI: 10.1021/acsmedchemlett.7b00233
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 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 improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

Keywords

GPR120; phenylpropanoic acid; type 2 diabetes.

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