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

• Published in: Journal of medicinal chemistry Vol. 54; no. 20; pp. 7385 - 7396
• Main Authors: Deng, Huayun, Hu, Haibei, He, Mingqian, Hu, Jieyu, Niu, Weijun, Ferrie, Ann M, Fang, Ye
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2011; Amer Chemical Soc
• Subjects: Arrestins - genetics; Arrestins - metabolism; beta-Arrestins; Cell Line; Chemistry, Medicinal; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Genes, Reporter; High-Throughput Screening Assays; Humans; Life Sciences & Biomedicine; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology & Pharmacy; Protein Transport - drug effects; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; CELLS; DYNAMIC MASS REDISTRIBUTION; BIOSENSOR; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200999f

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 EC50 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.