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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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The DMR characteristics of thieno[3,2-b]thiophene-2-carboxylic acid derivatives. (a–i) Compound 10 (32 μM), 11 (16 μM), 12 (16 μM), 13 (16 μM), 16a (250 nM), 16b (8 μM), 16c (8 μM), 16d (8 μM), and 16e (8 μM), respectively. Each compound induced DMR (Control) was compared to its corresponding DMR in the presence of 32 μM compound 17, the known GPR35 antagonist (Antagonist). The data represents mean ± sd from two independent measurements, each with four replicates (n = 8).
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fig6: The DMR characteristics of thieno[3,2-b]thiophene-2-carboxylic acid derivatives. (a–i) Compound 10 (32 μM), 11 (16 μM), 12 (16 μM), 13 (16 μM), 16a (250 nM), 16b (8 μM), 16c (8 μM), 16d (8 μM), and 16e (8 μM), respectively. Each compound induced DMR (Control) was compared to its corresponding DMR in the presence of 32 μM compound 17, the known GPR35 antagonist (Antagonist). The data represents mean ± sd from two independent measurements, each with four replicates (n = 8).

Mentions: Given that many compounds may exhibit polypharmacology and DMR measurement is integrative in nature, a compound-induced DMR may contain contributions from multiple targets/pathways with which the compound intervene. Thus, we first examined the specificity of the 18 compound-induced DMR using DMR antagonist assays. Each compound was assayed at a dose close to its respective EC80 or EC100 in the presence of compound 17. Results showed that compound 17 dose-dependently attenuated the DMR arising from all 18 compounds with similar potency (Table 1). However, compound 17 at 64 μM blocked the DMR induced by most compounds, except for compounds 5, 7, 8, 11, and 13, whose DMR were only partially suppressed (Figures 5 and 6). Together with the observed ability of these compounds to desensitize the cells to the zaprinast stimulation, these results suggest that the DMR induced by these compounds are mostly specific to GPR35, although we can not rule out the possibility of compounds 5, 7, 8, 11, and 13 to activate endogenous target(s) besides 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)

The DMR characteristics of thieno[3,2-b]thiophene-2-carboxylic acid derivatives. (a–i) Compound 10 (32 μM), 11 (16 μM), 12 (16 μM), 13 (16 μM), 16a (250 nM), 16b (8 μM), 16c (8 μM), 16d (8 μM), and 16e (8 μM), respectively. Each compound induced DMR (Control) was compared to its corresponding DMR in the presence of 32 μM compound 17, the known GPR35 antagonist (Antagonist). The data represents mean ± sd from two independent measurements, each with four replicates (n = 8).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: The DMR characteristics of thieno[3,2-b]thiophene-2-carboxylic acid derivatives. (a–i) Compound 10 (32 μM), 11 (16 μM), 12 (16 μM), 13 (16 μM), 16a (250 nM), 16b (8 μM), 16c (8 μM), 16d (8 μM), and 16e (8 μM), respectively. Each compound induced DMR (Control) was compared to its corresponding DMR in the presence of 32 μM compound 17, the known GPR35 antagonist (Antagonist). The data represents mean ± sd from two independent measurements, each with four replicates (n = 8).
Mentions: Given that many compounds may exhibit polypharmacology and DMR measurement is integrative in nature, a compound-induced DMR may contain contributions from multiple targets/pathways with which the compound intervene. Thus, we first examined the specificity of the 18 compound-induced DMR using DMR antagonist assays. Each compound was assayed at a dose close to its respective EC80 or EC100 in the presence of compound 17. Results showed that compound 17 dose-dependently attenuated the DMR arising from all 18 compounds with similar potency (Table 1). However, compound 17 at 64 μM blocked the DMR induced by most compounds, except for compounds 5, 7, 8, 11, and 13, whose DMR were only partially suppressed (Figures 5 and 6). Together with the observed ability of these compounds to desensitize the cells to the zaprinast stimulation, these results suggest that the DMR induced by these compounds are mostly specific to GPR35, although we can not rule out the possibility of compounds 5, 7, 8, 11, and 13 to activate endogenous target(s) besides 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