Abstract
Pactimibe sulfate, [7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate, a novel Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, was investigated in vitro and in vivo to characterize its potential. Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe. Kinetic analysis revealed pactimibe is a noncompetitive inhibitor of oleoyl-CoA (Ki value: 5.6 microM). Furthermore, pactimibe markedly inhibited cholesteryl ester formation (IC50: 6.7 microM) in human monocyte-derived macrophages, and inhibited copper-induced oxidation of low density lipoprotein more potently than probucol. Pactimibe exerted potent lipid-lowering and anti-atherosclerotic effects in atherogenic diet-fed hamsters. At doses of 3 and 10 mg/kg for 90 days, pactimibe decreased serum total cholesterol by 70% and 72%, and aortic fatty streak area by 79% and 95%, respectively. Despite similar cholesterol lowering, fatty streak area reduction was greater by 10 mg/kg. These results suggest that ACAT1/2 dual inhibitor pactimibe has anti-atherosclerotic potential beyond its plasma cholesterol-lowering activity.
MeSH terms
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Acyl Coenzyme A / metabolism
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Animals
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Arteriosclerosis / prevention & control*
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Catalysis / drug effects
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Cell Line
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Cell-Free System / enzymology
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Cell-Free System / metabolism
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Cholesterol Esters / metabolism
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Cricetinae
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Diet, Atherogenic
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Dose-Response Relationship, Drug
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Humans
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Hypercholesterolemia / classification
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Hypercholesterolemia / etiology
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Hypercholesterolemia / prevention & control
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacology
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Indoleacetic Acids / chemistry
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Indoleacetic Acids / pharmacology*
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Lipids / blood
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Lipoproteins, LDL / genetics
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / metabolism
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Oxidation-Reduction / drug effects
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Phosphatidylcholine-Sterol O-Acyltransferase / antagonists & inhibitors
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Phosphatidylcholine-Sterol O-Acyltransferase / metabolism
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Sterol O-Acyltransferase / antagonists & inhibitors*
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Sterol O-Acyltransferase / metabolism
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Sterol O-Acyltransferase 2
Substances
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Acyl Coenzyme A
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Cholesterol Esters
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Hypolipidemic Agents
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Indoleacetic Acids
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Lipids
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Lipoproteins, LDL
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oleoyl-coenzyme A
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pactimibe
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Sterol O-Acyltransferase
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sterol O-acyltransferase 1
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Phosphatidylcholine-Sterol O-Acyltransferase