title: A novel class of antagonists for the FFAs receptor GPR40.
abstract: 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Hu
authors.forename: Ling Yan
authors.initials: LY
authors.lastname: He
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gong
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yi Na
authors.initials: YN
authors.lastname: Lu
authors.forename: Qi Wei
authors.initials: QW
authors.lastname: Zhai
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hua Liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Wei Liang
authors.initials: WL
authors.lastname: Zhu
authors.forename: He Yao
authors.initials: HY
authors.lastname: Wang
mesh_terms: 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
chemical_list: C575478:DC26012; C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides