A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels.
BACKGROUND
Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial.


RESULTS
We developed and characterized a novel ACAT inhibitor, K-604. The IC(50) values of K-604 for human ACAT-1 and ACAT-2 were 0.45 and 102.85 micromol/L, respectively, indicating that K-604 is 229-fold more selective for ACAT-1. Kinetic analysis indicated that the inhibition was competitive with respect to oleoyl-coenzyme A with a K(i) value of 0.378 micromol/L. Exposure of human monocyte-derived macrophages to K-604 inhibited cholesterol esterification with IC(50) of 68.0 nmol/L. Furthermore, cholesterol efflux from THP-1 macrophages to HDL(3) or apolipoprotein A-I was enhanced by K-604. Interestingly, administration of K-604 to F1B hamsters on a high-fat diet at a dose of >or=1mg/kg suppressed fatty streak lesions without affecting plasma cholesterol levels.


CONCLUSIONS
K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis.
Ikenoya
Mami
M
Tokyo New Research Laboratories I, Pharmaceutical Division, Kowa Company Ltd., 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. m-ikenoy@kowa.co.jp
Yoshinaka
Yasunobu
Y
Kobayashi
Hideyuki
H
Kawamine
Katsumi
K
Shibuya
Kimiyuki
K
Sato
Fumiyasu
F
Sawanobori
Kimio
K
Watanabe
Takuya
T
Miyazaki
Akira
A
D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D016466:CHO Cells; D002454:Cell Differentiation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004041:Dietary Fats; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004951:Esterification; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000166:cytology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097587:Sterol O-Acyltransferase 2
D001562:Benzimidazoles; D002784:Cholesterol; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C520671:(2-(4-(2-benzimidazol-2ylthio)ethyl)piperazin-1yl)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide; C493492:sterol O-acyltransferase 1