Pharmacological Properties of R-755, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, in Cholesterol-Fed Rats, Hamsters and Rabbits
| Autor: | Yoshimitsu Matsui, Kenji Horiuchi, Kenji Yamamoto, Kazuo Kanai |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
medicine.medical_specialty Normal diet Arteriosclerosis Sterol O-acyltransferase Aorta Thoracic Thiophenes Cholesterol Dietary Rats Sprague-Dawley chemistry.chemical_compound In vivo Cricetinae Microsomes Internal medicine Tumor Cells Cultured medicine Animals Humans Urea Anilides Enzyme Inhibitors Triglycerides Hypolipidemic Agents Pharmacology Dose-Response Relationship Drug Mesocricetus Triglyceride Cholesterol Reverse cholesterol transport Rats Endocrinology Liver chemistry Microsome Rabbits Ex vivo Sterol O-Acyltransferase |
| Zdroj: | Japanese Journal of Pharmacology. 85:423-433 |
| ISSN: | 0021-5198 |
| Popis: | R-755 (N-(2,6-diethylphenyl)-#’-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][l]benzo-thiophen-2-yl]urea), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, has been characterized in vitro, ex vivo and in vivo. R-755 potently inhibited ACAT activities, with IC50 values from 2.5 to 64 nM, in rabbit intestinal microsomes and several cell lines (CaCo-2, THP-1 and J774A.1 cells). R-755 reduced serum cholesterol and triglyceride levels and liver cholesterol contents in cholesterol-fed rats, hamsters and rabbits. Rabbits were fed a high cholesterol diet for 2 weeks and further fed the same diet containing R-755 for 2 weeks. R-755 dose-dependently reduced cholesterol content and ACAT activity in the aorta. When phorbol 12-myristate 13-acetate-treated THP-1 and J774A.1 cells were incubated in the medium containing 20% of serum from rats administered R-755, the ACAT activities of the cells were inhibited. Rabbits were fed a high cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without R-755 for 8 weeks. R-755 dose-dependently reduced the surface area with atherosclerotic involvement and cholesterol contents in the aorta, although plasma cholesterol level did not differ from that in the control group. These results suggest that R-755 is a potent hypolipidemic agent and has a direct antiathero-sclerotic activity at the arterial wall. |
| Databáze: | OpenAIRE |
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