Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits.

Abstract

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.

• Authors: H Tanaka, I Ohtsuka, M Kogushi, T Kimura, T Fujimori, T Saeki, K Hayashi, H Kobayashi, T Yamada, H Hiyoshi
• Journal: Atherosclerosis (Atherosclerosis) Vol. 107 Issue 2 Pg. 187-201 (Jun 1994) ISSN: 0021-9150 [Print] Ireland
• PMID: 7980693 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anilides
• Phenylurea Compounds
• Cholestyramine Resin
• PD 128042
• E 5324
• Sterol O-Acyltransferase
• Probucol

Topics

• Anilides (therapeutic use)
• Animals
• Aorta, Thoracic (metabolism, pathology)
• Arteriosclerosis (drug therapy, metabolism, pathology)
• Cholestyramine Resin (therapeutic use)
• Dose-Response Relationship, Drug
• Lipid Metabolism
• Liver (metabolism, pathology)
• Male
• Phenylurea Compounds (therapeutic use)
• Probucol (therapeutic use)
• Rabbits
• Sterol O-Acyltransferase (antagonists & inhibitors, metabolism)
• Tunica Intima (pathology)
• Tunica Media (pathology)