PF-06427878 is an orally active, potent and selective diacylglycerol acyltransferase 2 inhibitor (human/rat DGAT2 IC50 = 99/202 nM; >470-fold selectivity over DGAT1, MGAT1/2/3) that inhibits DGAT2-dependent triglyceride (TG) synthesis in primary human hepatocytes (IC50 = 11.6 nM in the presence of DGAT1 inhibitor PF-04620110). PF-06427878 reduces hepatic and circulating plasma TG levels as well as lipogenic gene expression in rats maintained on a Western-type diet (0.3-30 mg/kg bid. po.). Likewise, PF-06427878 significantly improves steatosis and hepatocellular ballooning with a decrease in lobular inflammation in a murine nonalcoholic steatohepatitis (NASH) model (2 or 20 mg/kg bid. po.).
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11 - Combustible Solids
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WGK 3
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Not applicable
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Nonalcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatocyte triglycerides, the synthesis of which is catalyzed by diacylglycerol acyltransferases (DGATs). Here, we investigate DGAT2 as a potential therapeutic target using an orally administered, selective DGAT2 inhibitor, PF-06427878. Treatment with
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