Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe.
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.
Kitayama
Ken
K
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. kitaya@sankyo.co
Tanimoto
Tatsuo
T
Koga
Teiichiro
T
Terasaka
Naoki
N
Fujioka
Tomoyuki
T
Inaba
Toshimori
T
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D002474:Cell-Free System / Q000201:enzymology / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D004036:Diet, Atherogenic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006937:Hypercholesterolemia / Q000145:classification / Q000209:etiology / Q000517:prevention & control; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000737:chemistry / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
D000214:Acyl Coenzyme A; D002788:Cholesterol Esters; D000960:Hypolipidemic Agents; D007210:Indoleacetic Acids; D008055:Lipids; D008077:Lipoproteins, LDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C017585:oleoyl-coenzyme A; C509302:pactimibe; C493492:sterol O-acyltransferase 1