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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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DMR characteristics of known GPR35 ligands in HT29. (a) Structure of a known GPR35 antagonist compound 17. (b) The DMR arising from zaprinast (500 nM), the antagonist compound 17 (32 μM), and zaprinast (500 nM) + compound 17 (32 μM). (c) The dose-dependent blockage of the zaprinast DMR by compound 17. The data represents mean ± sd (standard deviation) from two independent measurements, each in duplicate (n = 4).
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fig1: DMR characteristics of known GPR35 ligands in HT29. (a) Structure of a known GPR35 antagonist compound 17. (b) The DMR arising from zaprinast (500 nM), the antagonist compound 17 (32 μM), and zaprinast (500 nM) + compound 17 (32 μM). (c) The dose-dependent blockage of the zaprinast DMR by compound 17. The data represents mean ± sd (standard deviation) from two independent measurements, each in duplicate (n = 4).

Mentions: Because human colorectal adenocarcinoma cell line HT29 endogenously expresses functional GPR35,(22) this cell line was chosen to screen GPR35 agonists. The known GPR35 agonist zaprinast was used as a reference agonist. Previously, we have showed that zaprinast resulted in a robust DMR with an EC50 of 0.16 ± 0.02 μM and internalization of GPR35 in HT29.(22) Compound 17, a known GPR35 antagonist, did not lead to any detectable DMR in HT29, but dose-dependently blocked the zaprinast DMR with an IC50 of 10.5 ± 0.3 μM (n = 4) (Figure1). At the highest dose (64 μM), compound 17 almost completely blocked the zaprinast DMR. These results suggest that the zaprinast-induced DMR in HT29 is specific to the activation of GPR35.


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)

DMR characteristics of known GPR35 ligands in HT29. (a) Structure of a known GPR35 antagonist compound 17. (b) The DMR arising from zaprinast (500 nM), the antagonist compound 17 (32 μM), and zaprinast (500 nM) + compound 17 (32 μM). (c) The dose-dependent blockage of the zaprinast DMR by compound 17. The data represents mean ± sd (standard deviation) from two independent measurements, each in duplicate (n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: DMR characteristics of known GPR35 ligands in HT29. (a) Structure of a known GPR35 antagonist compound 17. (b) The DMR arising from zaprinast (500 nM), the antagonist compound 17 (32 μM), and zaprinast (500 nM) + compound 17 (32 μM). (c) The dose-dependent blockage of the zaprinast DMR by compound 17. The data represents mean ± sd (standard deviation) from two independent measurements, each in duplicate (n = 4).
Mentions: Because human colorectal adenocarcinoma cell line HT29 endogenously expresses functional GPR35,(22) this cell line was chosen to screen GPR35 agonists. The known GPR35 agonist zaprinast was used as a reference agonist. Previously, we have showed that zaprinast resulted in a robust DMR with an EC50 of 0.16 ± 0.02 μM and internalization of GPR35 in HT29.(22) Compound 17, a known GPR35 antagonist, did not lead to any detectable DMR in HT29, but dose-dependently blocked the zaprinast DMR with an IC50 of 10.5 ± 0.3 μM (n = 4) (Figure1). At the highest dose (64 μM), compound 17 almost completely blocked the zaprinast DMR. These results suggest that the zaprinast-induced DMR in HT29 is specific to the activation of GPR35.

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
Related in: MedlinePlus