title: A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels.
abstract: 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.
authors.affiliation: Tokyo New Research Laboratories I, Pharmaceutical Division, Kowa Company Ltd., 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. m-ikenoy@kowa.co.jp
authors.forename: Mami
authors.initials: M
authors.lastname: Ikenoya
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshinaka
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kawamine
authors.forename: Kimiyuki
authors.initials: K
authors.lastname: Shibuya
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Sato
authors.forename: Kimio
authors.initials: K
authors.lastname: Sawanobori
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Miyazaki
mesh_terms: 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
chemical_list: 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