A Novel Acyl-CoA: Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor, GSK2973980A, Inhibits Postprandial Triglycerides and Reduces Body Weight in a Rodent Diet-induced Obesity Model
Journal Title: Journal of Pharmaceutical Research International - Year 2017, Vol 18, Issue 6
Abstract
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 and Affiliations
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, Mui Cheung
Keywords
Related Articles
- EP ID EP313127
- DOI 10.9734/JPRI/2017/36835
- Views 96
- Downloads 0
Antibacterial Activity of Pennisetum glaucum Crude Extracts and Pre-purified Fractions against Selected Pathogenic Microorganisms
Background: Penisetum glaucum is one of the earliest indigenous food crops in East Africa. Pearl millet contains numerous phytocompounds. Isolation and characterization of secondary metabolites from pearl millet and eval...
Free Radical Scavenging Activity and Protein Concentration and Profile of the Blowfly Maggot (Lucilia robineau) Excretion/Saliva Extract
Aim: The aim of this study was to determine the free radical scavenging activity, Protein concentration and profile of Blowfly maggot (Lucilia robineau) excretion/secretion (ES). Place and Duration of Study: Maggot sampl...
Effects of Wild Artemisia herba-alba Essential Oil on Biofilm-Forming Bacteria
Aims: The aim of the present study was to determine the effects of essential oil of wild Artemisia herba-alba grown in south Jordan on biofilm-forming bacteria. Study Design: Seven bacterial clinical isolates were used i...
Synthesis of Silver Nanoparticles by Sodium Borohydride Reduction Method: Optimization of Conditions for High Anti-staphylococcal Activity
Aim: The aim of this research was to optimize the reaction conditions for the production of silver nanoparticles sufficiently bioactive for incorporation into pharmaceutical gels. Methods: Silver nanoparticles were prep...
The Effect of Creatine Supplementation with Resistance Training on the Levels of Renin and Aldosterone in Wistar Rats
Objective: The aim of the present study was to compare the effect of creatine 2% and 5% supplementation with resistance training on the levels of renin and aldosterone Methods: The 60 Wistar rats were randomly assigned...