Applications
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In HepG2 cell lysates, A-922500 (1 μM) inhibited about 99% of recombinant DGAT1 enzymatic activity. Exposure of HepG2 cells to A-922500 dose-dependently inhibited TG synthesis (stable isotope-labeled triolein; 13C18-oleoyl, 13C18-oleoyl, 13C18-oleoyl). In HEK293 cells expressing DGAT1, A-922500 inhibited [13C18]oleoyl triolein incorporation with the IC50 values of 17 nM.
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Application
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In Zucker fatty rats and diet-induced dyslipidemic hamsters, oral administration of A 922500 (3 mg/kg, 14 days) significantly reduced serum triglycerides and free fatty acid levels. A 922500 (3 mg/kg) significantly increased high-density lipoprotein-cholesterol. In DIO mice, A 922500 induced weight loss and reduced liver triglycerides when dosed chronically. A 922500 depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice. A 922500 (0.03, 0.3 and 3 mg/kg, p.o.) dose-dependently attenuated the maximal postprandial rise in serum triglyceride concentrations.
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References:
[1]. Qi J, Lang W, Geisler J G, et al. The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and-2. Journal of lipid research, 2012, 53(6): 1106-1116.
[2]. Qi J, Lang W, Giardino E, et al. High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity. Journal of lipid research, 2010, 51(12): 3559-3567.
[3]. Zhao G, et al. Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J Med Chem. 2008, 51(3), 380-383.
[4]. King, Andrew J.; Segreti, Jason A.; Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster. Journal of Pharmacology and Experimental Therapeutics (2009), 330(2), 526-531. [5]. King AJ, Segreti JA, Larson KJ, Souers AJ, Kym PR, Reilly RM, Collins CA, Voorbach MJ, Zhao G, Mittelstadt SW, Cox BF.In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia.Eur J Ph
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