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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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Representative DMR signals of GPR35 agonists identified. (a) The dose-dependent DMR induced by 1, (b) the dose-dependent DMR induced by 16a, (c) the amplitudes of the DMR induced by 2-(4-methylfuran-2(5H)-ylidene)malononitrile derivatives as a function of doses, and (d) the amplitudes of the DMR induced by thieno[3,2-b]thiophene-2-carboxylic acid derivatives as a function of doses.
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fig10: Representative DMR signals of GPR35 agonists identified. (a) The dose-dependent DMR induced by 1, (b) the dose-dependent DMR induced by 16a, (c) the amplitudes of the DMR induced by 2-(4-methylfuran-2(5H)-ylidene)malononitrile derivatives as a function of doses, and (d) the amplitudes of the DMR induced by thieno[3,2-b]thiophene-2-carboxylic acid derivatives as a function of doses.

Mentions: To further examine structure and activity analysis, we determined the potency of all 18 compounds to trigger DMR signals in HT29 cells using DMR assays. The results showed that all compounds gave rise to a clear dose-dependent response (Figure10). All compounds led to a saturable response at the dose ranges examined. However, there are significant differences in potency, efficacy, and DMR characteristics of these compounds (Table 1, Figures 5 and 6).


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)

Representative DMR signals of GPR35 agonists identified. (a) The dose-dependent DMR induced by 1, (b) the dose-dependent DMR induced by 16a, (c) the amplitudes of the DMR induced by 2-(4-methylfuran-2(5H)-ylidene)malononitrile derivatives as a function of doses, and (d) the amplitudes of the DMR induced by thieno[3,2-b]thiophene-2-carboxylic acid derivatives as a function of doses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig10: Representative DMR signals of GPR35 agonists identified. (a) The dose-dependent DMR induced by 1, (b) the dose-dependent DMR induced by 16a, (c) the amplitudes of the DMR induced by 2-(4-methylfuran-2(5H)-ylidene)malononitrile derivatives as a function of doses, and (d) the amplitudes of the DMR induced by thieno[3,2-b]thiophene-2-carboxylic acid derivatives as a function of doses.
Mentions: To further examine structure and activity analysis, we determined the potency of all 18 compounds to trigger DMR signals in HT29 cells using DMR assays. The results showed that all compounds gave rise to a clear dose-dependent response (Figure10). All compounds led to a saturable response at the dose ranges examined. However, there are significant differences in potency, efficacy, and DMR characteristics of these compounds (Table 1, Figures 5 and 6).

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