A novel class of antagonists for the FFAs receptor GPR40.
The free fatty acid receptor, GPR40, is implicated in the pathophysiology of type 2 diabetes, and is a new potential drug target for the treatment of type 2 diabetes. Its antagonist is thought to be not only a useful chemical probe for further exploring the function of GPR40 but also a lead structure for drug development. With virtual screening based on a homology model followed by a cell-based calcium mobilization assay, we found that sulfonamides are a new class of small organic antagonists for GPR40. One of the compounds, DC260126, dose-dependently inhibited GPR40-mediated Ca(2+) elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid (IC(50): 6.28+/-1.14, 5.96+/-1.12, 7.07+/-1.42, 4.58+/-1.14 microM, respectively), reduced GTP-loading and ERK1/2 phosphorylation stimulated by linoleic acid in GPR40-CHO cells, suppressed palmitic acid potentiated glucose-stimulated insulin secretion, and negatively regulated GPR40 mRNA expression induced by oleic acid in Min6 cells.
Hu
Hui
H
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
He
Ling Yan
LY
Gong
Zhen
Z
Li
Ning
N
Lu
Yi Na
YN
Zhai
Qi Wei
QW
Liu
Hong
H
Jiang
Hua Liang
HL
Zhu
Wei Liang
WL
Wang
He Yao
HY
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
C575478:DC26012; C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides