Discovery of 2-(4-Methylfuran-2(5H)-ylidene)malononitrile and Thieno[3,2-b]thiophene-2-carboxylic Acid Derivatives as G Protein-Coupled Receptor 35 (GPR35) Agonists
| Autor: | Huayun Deng, Haibei Hu, Jieyu Hu, Ye Fang, Ann M. Ferrie, Mingqian He, Weijun Niu |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Arrestins medicine.drug_class Stereochemistry Carboxylic acid Thiophenes Article Cell Line Receptors G-Protein-Coupled Structure-Activity Relationship chemistry.chemical_compound Genes Reporter Nitriles Drug Discovery medicine Humans Structure–activity relationship Furans beta-Arrestins Malononitrile chemistry.chemical_classification Beta-Arrestins High-Throughput Screening Assays Protein Transport chemistry Molecular Medicine G-Protein Coupled Receptor 35 Zaprinast GPR35 |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm200999f |
| Popis: | Screening with dynamic mass redistribution (DMR) assays in a native cell line HT-29 led to identification of two novel series of chemical compounds, 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives, as GPR35 agonists. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively. Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist. DMR antagonist assays, knockdown of GPR35 with interference RNA, receptor internalization assays, and Tango β-arrestin translocation assays confirmed that the agonist activity of these ligands is specific to GPR35. The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology. |
| Databáze: | OpenAIRE |
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