Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the terminal step in triacylglycerol (TAG) synthesis. Studies performed with antisense oligonucleotides (ASO) in rodent models have shown beneficial effects of DGAT2 blockade on both glycemic control and plasma lipid profile, suggesting the potential utility of DGAT2 inhibitors for the treatment of metabolic disease. However, to date, the pharmacologic effects of DGAT2 inhibitors have not been described.  This presentation will describe hit-to-lead medicinal chemistry efforts to identify novel DGAT2 inhibitors which ultimately led to the discovery of the pre-clinical candidate. To our knowledge, the pre-clinical candidate discovered is the first small molecule DGAT2 inhibitor to be evaluated in preclinical models of metabolic disease. Our findings demonstrate that inhibition of DGAT2 has the potential to impact multiple components of metabolic disease.  Preclinical characterization, including in vitro/in vivo pharmacology, ADME, and safety profiles, of the preclinical candidate, will be discussed.

Discovery of novel small molecule inhibitors of diacylglycerol acyltransferase 2 (DGAT2)

248th National Meeting (2014)

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