Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits.
E5324, n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea, a novel and orally absorbable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated for its antiatherosclerotic and antihyperlipidemic effects in cholesterol-fed hypercholesterolemic rabbits. When administered concurrently with a high-cholesterol (0.5% cholesterol) diet for 12 weeks, E5324 (0.0025%, 0.005% and 0.01% in diet) lowered plasma total cholesterol levels dose-dependently (by about 55%-87% at the end of the experiment compared with the control) and also reduced atherosclerotic plaque formation (about 90% reduction at the highest dose; P < 0.01). In pre-established hypercholesterolemic rabbits, which had been pre-fed a high-cholesterol diet for 8 weeks, E5324 administered in the same diet at a dose of 0.005%, 0.01% or 0.02% for 4 weeks significantly reduced plasma cholesterol levels dose-dependently. Cholesterol content and ACAT activity in the aortic arch were also decreased (by about 72% and 58% at the highest dose, respectively) compared with the control. Another ACAT inhibitor, CI-976, had a similar action, but cholestyramine and probucol (2% and 1% in diet, respectively) lacked anti-atherosclerotic activity in this model. Furthermore, when pre-established hypercholesterolemic rabbits were fed normal rabbit chow diet with or without 0.02% E5324 for 4 weeks, changes in plasma cholesterol levels were similar in both E5324-treated and control groups. On the other hand, E5324 significantly reduced cholesterol content and ACAT activity in the aortic arch (by about 52% and 50%, respectively) compared with the control group. These results indicate that E5324 not only has hypocholesterolemic activity, but also may have a direct effect on the arterial wall in experimental atherosclerosis.
Tanaka
H
H
Eisai Tsukuba Research Laboratories, Eisai Company Ltd., Ibaraki, Japan.
Ohtsuka
I
I
Kogushi
M
M
Kimura
T
T
Fujimori
T
T
Saeki
T
T
Hayashi
K
K
Kobayashi
H
H
Yamada
T
T
Hiyoshi
H
H
D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002792:Cholestyramine Resin / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011341:Probucol / Q000627:therapeutic use; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D000813:Anilides; D010671:Phenylurea Compounds; D002792:Cholestyramine Resin; C069304:PD 128042; C090175:E 5324; D002785:Sterol O-Acyltransferase; D011341:Probucol