Discovery of 2H-Chromen-2-one Derivatives as G Protein-Coupled Receptor-35 Agonists

  • J Med Chem. 2017 Jan 12;60(1):362-372. doi: 10.1021/acs.jmedchem.6b01431.
Lai Wei  1 ,  Jixia Wang  1 ,  Xiuli Zhang  1  2 ,  Ping Wang  1 ,  Yaopeng Zhao  1 ,  Jiaqi Li  1 ,  Tao Hou  1 ,  Lala Qu  1 ,  Liying Shi  1 ,  Xinmiao Liang  1  2 ,  Ye Fang  3
Affiliations
  • 1. Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
  • 2. Co-innovation Center of Neuroregeneration, Nantong University , Nantong 226019, China.
  • 3. Biochemical Technologies, Science and Technology Division, Corning , New York 14831, United States.
PMID: 27976894 DOI: 10.1021/acs.jmedchem.6b01431
Abstract

A family of 2H-chromen-2-one derivatives were identified as G protein-coupled receptor-35 (GPR35) agonists using dynamic mass redistribution assays in HT-29 cells. The compounds with 1H-tetrazol-5-yl in 3-substituted position displayed higher potency than the corresponding carboxyl analogs, and the hydroxyl group in the 7-position also played an important role in GPR35 agonistic activity. 6-Bromo-7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one (50) was found to be the most potent GPR35 Agonist with an EC50 of 5.8 nM. Calculating the physicochemical properties of compounds with moderate to high potency suggested that compounds 30, 50, and 51 showed good druggability. This study provides a novel series of GPR35 agonists, and compound 50 may be a powerful tool to study GPR35.

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