pactimibe and Arteriosclerosis

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.

Topics: Acyl Coenzyme A; Animals; Arteriosclerosis; Catalysis; Cell Line; Cell-Free System; Cholesterol Esters; Cricetinae; Diet, Atherogenic; Dose-Response Relationship, Drug; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoleacetic Acids; Lipids; Lipoproteins, LDL; Macrophages; Monocytes; Oxidation-Reduction; Phosphatidylcholine-Sterol O-Acyltransferase; Rabbits; Rats; Rats, Sprague-Dawley; Sterol O-Acyltransferase; Sterol O-Acyltransferase 2