DC260126

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Background

DC260126 is a GPR40 antagonist [1][2]. The G protein-coupled receptor 40 (GPR40), also known as FFAR1, is a free fatty acid receptor, which is activated by saturated and unsaturated long or medium chain fatty acids in pancreatic β-cells. Free fatty acids (FFAs) are essential regulators of normal β-cell and play important roles in the pathogenesis of β-cell dysfunction in type 2 diabetes. GPR40 is a new potential drug target for the treatment of type 2 diabetes [1][2]. DC260126 is a FFAR1/GPR40 antagonist. DC260126 dose-dependently inhibited GPR40-mediated Ca2+ elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid with IC50 values of 6.28 ± 1.14, 5.96 ± 1.12, 7.07 ± 1.42 and 4.58 ± 1.14 μM, respectively. In GPR40-CHO cells, DC260126 dose-dependently reduced GTP-loading and ERK1/2 phosphorylation stimulated by linoleic acid. In Min6 cells, DC260126 inhibited palmitic acid potentiated glucose-stimulated insulin secretion, and negatively regulated GPR40 mRNA expression induced by oleic acid [1]. In obese diabetic db/db mice, DC260126 (10 mg/kg, 21-days treatment) significantly inhibited glucose stimulated insulin secretion, reduced blood insulin level and improved insulin sensitivity. DC260126 also reduced the apoptotic rate of pancreatic β-cells and the proinsulin/insulin ratio [2].

[1]. Hu H, He LY, Gong Z, et al. A novel class of antagonists for the FFAs receptor GPR40. Biochem Biophys Res Commun. 2009 Dec 18;390(3):557-63.
[2]. Sun P, Wang T, Zhou Y, et al. DC260126: a small-molecule antagonist of GPR40 that protects against pancreatic β-Cells dysfunction in db/db mice. PLoS One. 2013 Jun 11;8(6):e66744.