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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.

Deng H, Hu H, He M, Hu J, Niu W, Ferrie AM, Fang Y - J. Med. Chem. (2011)

Bottom Line: 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.The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.

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.

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Screening GPR35 agonists. (a) The DMR amplitudes of compounds in the library as a function of compounds. (b) The DMR signals induced by zaprinast after the cells were prestimulated with compounds in the library. (c) The correlation between the compound DMR in native cells and the zaprinast DMR in the compound-pretreated cells.
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fig2: Screening GPR35 agonists. (a) The DMR amplitudes of compounds in the library as a function of compounds. (b) The DMR signals induced by zaprinast after the cells were prestimulated with compounds in the library. (c) The correlation between the compound DMR in native cells and the zaprinast DMR in the compound-pretreated cells.

Mentions: To identify hits, the amplitudes at 8 min poststimulation of all compound-induced responses were determined and used as a basis for hit identification in the agonist screen. This is because zaprinast at a saturating dose (1 μM) led to a maximal response peaked at about 8 min poststimulation (246 ± 11 pm, n = 32). Using the compound DMR amplitudes greater than 30% of the zaprinast response as the hit identification criteria, 55 hits in total were identified (Figure2a).


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.

Deng H, Hu H, He M, Hu J, Niu W, Ferrie AM, Fang Y - J. Med. Chem. (2011)

Screening GPR35 agonists. (a) The DMR amplitudes of compounds in the library as a function of compounds. (b) The DMR signals induced by zaprinast after the cells were prestimulated with compounds in the library. (c) The correlation between the compound DMR in native cells and the zaprinast DMR in the compound-pretreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198121&req=5

fig2: Screening GPR35 agonists. (a) The DMR amplitudes of compounds in the library as a function of compounds. (b) The DMR signals induced by zaprinast after the cells were prestimulated with compounds in the library. (c) The correlation between the compound DMR in native cells and the zaprinast DMR in the compound-pretreated cells.
Mentions: To identify hits, the amplitudes at 8 min poststimulation of all compound-induced responses were determined and used as a basis for hit identification in the agonist screen. This is because zaprinast at a saturating dose (1 μM) led to a maximal response peaked at about 8 min poststimulation (246 ± 11 pm, n = 32). Using the compound DMR amplitudes greater than 30% of the zaprinast response as the hit identification criteria, 55 hits in total were identified (Figure2a).

Bottom Line: 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.The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.

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.

Show MeSH