HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits.
HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine.
Asami
Y
Y
Research Laboratories, Taisho Pharmaceutical Co. Ltd., Ohmiya, Saitama, Japan. S10960@ccam.taisho.co.jp
Yamagishi
I
I
Murakami
S
S
Araki
H
H
Tsuchida
K
K
Higuchi
S
S
D000083:Acetanilides / Q000627:therapeutic use*; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D018450:Disease Progression; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000083:Acetanilides; D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; C092284:HL 004; D008055:Lipids; D002784:Cholesterol; D002785:Sterol O-Acyltransferase