Background and Aim: Acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme catalyzing the final step of triglyceride (TG) synthesis and is implicated in fat absorption and disposition. However, development of several DGAT1 inhibitors has been hampered due to unacceptable gastrointestinal (GI) tolerability observed in clinical trials. Our aim is to develop a novel, potent and selective DGAT1 inhibitor that reduces plasma TG levels and body weight with acceptable GI tolerability in a rodent model of obesity.
Study Design: In vitro enzyme and cellular assays as well as in vivo experimental studies in mice and rat examining the effect of drugs on triglycerides, fecal fat, body weight and food intake.
Place and Duration of Study: Virtual proof of concept, GSK USA & Cellzome, GSK Germany and Collaborative research, GVK, India between 2011-2017.
Methodology: A radiometric assay of TG formation evaluated DGAT activity and a thermal shift assay determined target specificity. Fasted mice received an oral corn oil bolus to model hypertriglyceridemia. Intralipid administration in fasted rats was used to evaluate triglyceride clearance. Mice were fed a high fat diet to induce obesity.
Results: Herein, we describe GSK2973980A as a novel, potent and selective DGAT1 inhibitor that reduced plasma TG levels in postprandial lipid excursion and impaired clearance studies in rodents and reduced body weight and food intake in obese mice. Interestingly, robust plasma TG reduction was accompanied by varying degrees of fecal lipid excretion. Alternate dosing via the subcutaneous route maintained a significant effect on plasma TG reduction with no altered fecal lipid excretion, suggesting GI tolerability may be modulated by limiting local GI exposure of DGAT1 inhibitors.
Conclusion: Our data suggest that the impaired TG clearance model in the rat can be used to identify DGAT1 inhibitors with potentially better GI tolerability.
Authors Sanjay Kumar, Vijaya G. Tirunagaru, Jennifer Ariazi, Amit Awasthi, Venkatesh Babu Jayaraman, Premkumar Arumugam, Mahesh Yanamandra, Sayan Mitra, Sudhir Tiwari, Raghuram S. Tangirala, Thilo Werner, Douglas Thomson, Giovanna Bergamini and Mui Cheung