RP-64477 is a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). RP-64477 inhibits ACAT activity with IC50 of 113 nM, 503 nM, and 180 nM in human intestinal (CaCo-2), hepatic (HepG2) and monocytic
RP-64477 is a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). RP-64477 inhibits ACAT activity with IC50 of 113 nM, 503 nM, and 180 nM in human intestinal (CaCo-2), hepatic (HepG2) and monocytic (THP-1) cell assays, respectively.
[1] A A Bello, et al. Biochem Pharmacol. 1996 Feb 23;51(4):413-21.
Cell experiment: | ACAT activity is determined in CaCo-2 cells. Cells cultured in 6-well plates are preincubated for 2 hr in 2 mL of Medium 199 supplemented with 10 mM Hepes, pH 7.4, and cholesterol-rich micelles in the presence or absence of RP-64477 that has been initially prepared in neat DMSO. The final concentration of DMSO in the culture medium is 0.2% v/v. Preincubation medium is then replaced with the same medium containing 50 μM [14C] oleic acid complexed with 17 μM bovine serum albumin (fatty acid-free) and cells incubated for a further 2 hr. RP-64477 or vehicle is present during both incubations[1]. |
Animal experiment: | Hypocholesterolaemic activity of RP-64477 is investigated by administering RP-64477 (0.00l% to 0.03% w/w by diet) to rats maintained for 3 days on powdered laboratory diet supplemented with cholesterol/cholic acid. Animals are then killed by asphyxiation in carbon dioxide, and terminal blood samples taken by cardiac puncture into a heparinised syringe for preparation of plasma. Plasma cholesterol concentrations are determined enzymatically using standard assay kits. Hypocholesterolaemic activity of RP-64477 in rabbits is investigated by administering RP-64477 at doses of 1, 3, 10, and 30 mg/kg b.i.d. for 7 days to animals receiving standard laboratory diet supplemented with cholesterol. Blood samples are obtained from the central ear artery on days 0 (predosing), 4, and 7 of the study[1]. |
参考文献: [1]. Bello AA, et al. RP 64477: a potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase with low systemic bioavailability. Biochem Pharmacol. 1996 Feb 23;51(4):413-21. | |
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