T863 is an orally active, selective and potent DGAT1 (Acyl-CoA:diacylglycerol acyltransferase 1) inhibitor that interacts with the acyl-CoA binding site of DGAT1, and inhibits triacylglycerol synthesis in cells.
Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. T863 is a potent and specific DGAT1 inhibitor with respect to oleoyl-CoA with IC50 values of 49 nM and 17 nM in the CPM fluorescent assay and the TLC assay, respectively. T863 showed a dose-dependent inhibition of the binding of radiolabeled oleoyl-CoA to DGAT1. T863 caused a dose-dependent inhibition of cellular triacylglycerol (TAG) formation in HEK293-DGAT1 cells with an IC50 of 122 nM. In an acute lipid challenge model using C57/BL6 mice, administration of the corn oil bolus resulted in a significant, 60% increase in serum triglyceride levels in vehicle-treated animals, while no increase was observed in mice treated with 10 mg/kg T863 indicating T863 inhibits acute lipid absorption. Administration of T863 (30 mg/kg for 15 days) to DIO (diet-induced obese) mice caused a reduction in body weight, which reached statistical significance by the 13th day of treatment. Moreover, T863-treated DIO mice showed a modest improvement in clearing glucose from peripheral circulation[3].
作用机制
T863 binds to the oleoyl-CoA binding site of DGAT1 bound with 1,2-DOG[3].
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