Limits...
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.

Show MeSH
The dose-dependent desensitization by GPR35 agonists identified to the repeated stimulation with zaprinast (1 μM). (a,b) Real-time zaprinast DMR after pretreatment with 1 (a) and 2 (b), respectively, and (c) and (d) dose-dependent desensitization by thieno[3,2-b]thiophene-2-carboxylic acid derivatives (c) and thieno[3,2-b]thiophene-2-carboxylic acid derivatives (d), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198121&req=5

fig11: The dose-dependent desensitization by GPR35 agonists identified to the repeated stimulation with zaprinast (1 μM). (a,b) Real-time zaprinast DMR after pretreatment with 1 (a) and 2 (b), respectively, and (c) and (d) dose-dependent desensitization by thieno[3,2-b]thiophene-2-carboxylic acid derivatives (c) and thieno[3,2-b]thiophene-2-carboxylic acid derivatives (d), respectively.

Mentions: The DMR desensitization assays showed that all compounds also dose-dependently desensitized the cells to the repeated stimulation with 1 μM zaprinast, and the rank order of their apparent IC50 values to desensitize the cells is similar to that of their respective EC50 values (Figure11). This suggests that all compounds activate GPR35 as zaprinast does. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (1, YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (16a, YE210)(26) were the two most potent agonists, and their respective EC50 was 32.5 ± 1.7 nM (n = 4) and 63.7 ± 4.1 nM (n = 4), both of which are more potent than zaprinast (163 ± 19 nM, n = 4).


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 dose-dependent desensitization by GPR35 agonists identified to the repeated stimulation with zaprinast (1 μM). (a,b) Real-time zaprinast DMR after pretreatment with 1 (a) and 2 (b), respectively, and (c) and (d) dose-dependent desensitization by thieno[3,2-b]thiophene-2-carboxylic acid derivatives (c) and thieno[3,2-b]thiophene-2-carboxylic acid derivatives (d), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig11: The dose-dependent desensitization by GPR35 agonists identified to the repeated stimulation with zaprinast (1 μM). (a,b) Real-time zaprinast DMR after pretreatment with 1 (a) and 2 (b), respectively, and (c) and (d) dose-dependent desensitization by thieno[3,2-b]thiophene-2-carboxylic acid derivatives (c) and thieno[3,2-b]thiophene-2-carboxylic acid derivatives (d), respectively.
Mentions: The DMR desensitization assays showed that all compounds also dose-dependently desensitized the cells to the repeated stimulation with 1 μM zaprinast, and the rank order of their apparent IC50 values to desensitize the cells is similar to that of their respective EC50 values (Figure11). This suggests that all compounds activate GPR35 as zaprinast does. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (1, YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (16a, YE210)(26) were the two most potent agonists, and their respective EC50 was 32.5 ± 1.7 nM (n = 4) and 63.7 ± 4.1 nM (n = 4), both of which are more potent than zaprinast (163 ± 19 nM, n = 4).

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