Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction[3]. AZD7687 is a potent and selective DGAT1 inhibitor with an IC50 value of 80 nM to human DGAT1recombinant. In in vitro radioligand binding and enzyme assays, AZD7687 showed inhibition of acyl-CoA: cholesterol acetyltransferase (79% at 10μM), fatty acid amide hydrolase (IC50=3.7μM), muscarinic M2 receptor (IC50=80.5μM), and phosphodiesterase PDE10A1 (IC50=5.5μM). In the rat oral lipid tolerance test (OLTT) assay, AZD7687 was able to reduce the formation of TAG (triacylglycerol) in adipose tissue (measured as TAG/DAG ratio) in an exposure dependent manner. In addition, AZD7687 was shown to have beneficial effects in several preclinical metabolic disease models (e.g., enhanced GLP-1 secretion, delayed gastric emptying, reduced food intake, improved insulin sensitivity, reduced atherosclerosis)[4]. Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Dose-dependent reductions in postprandial serum triacylglycerol (TAG) were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01)[5].
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