title: 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.
abstract: 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.
authors.affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.
authors.forename: Huayun
authors.initials: H
authors.lastname: Deng
authors.forename: Haibei
authors.initials: H
authors.lastname: Hu
authors.forename: Mingqian
authors.initials: M
authors.lastname: He
authors.forename: Jieyu
authors.initials: J
authors.lastname: Hu
authors.forename: Weijun
authors.initials: W
authors.lastname: Niu
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ferrie
authors.forename: Ye
authors.initials: Y
authors.lastname: Fang
mesh_terms: D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: C568964:2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile; C568965:6-bromo-3-methylthieno(3,2-b)thiophene-2-carboxylic acid; D019390:Arrestins; D005663:Furans; C111379:GPR35 protein, human; D009570:Nitriles; D043562:Receptors, G-Protein-Coupled; D013876:Thiophenes; D000071557:beta-Arrestins