Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters.

Abstract

The hypolipidemic and antioxidant effects of N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide (CAS 178469-71-1, KY-455), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were examined in hyperlipidemic rabbits and normolipidemic hamsters. KY-455 inhibited rabbit intestinal, hepatic, macrophage and adrenal ACAT with IC50 values of 0.4, 0.9, 2.9 and 4.1 micromol/l, respectively. KY-455 also inhibited rabbit plasma and LDL-peroxidation (IC50: 0.4 and 1.7 micromol/l, respectively). In rabbits fed a high-cholesterol diet, treatment with KY-455 (30 mg/kg/day) for 8 days markedly lowered serum esterified, free, low-density lipoprotein (LDL)-cholesterol, and hepatic esterified cholesterol levels. KY-455 tended to inhibit ex vivo hepatic ACAT activity 5 h after the final administration. KY-455 also inhibited ex vivo peroxidation of plasma lipids 1 and 5 h after the final administration in rabbits. In normolipidemic hamsters fed a regular diet, treatment with KY-455 (30 mg/kg, twice a day) for 4 days significantly reduced serum esterified, free and LDL-cholesterol, and hepatic esterified and free cholesterol levels. A single administration of KY-455 (30 mg/kg) significantly inhibited ex vivo hepatic ACAT activity in hamsters. In conclusion, KY-455 showed in vitro inhibitory effects on LDL-peroxidation and macrophage ACAT activity at similar concentrations, and in vivo hypolipidemic and ex vivo antioxidative effects at the same dose. Long-term administration of KY-455 is expected to prevent the progress of atherosclerosis by lowering plasma lipid levels, inhibiting both LDL-oxidation and accumulation of cholesterol in macrophages.

• Authors: Shohei Nakamura, Shoji Kamiya, Hiroaki Shirahase, Mamoru Kanda, Akihisa Yoshimi, Tadatsugu Tarumi, Kazuyoshi Kurahashi
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 54 Issue 2 Pg. 102-8 ( 2004) ISSN: 0004-4172 [Print] Germany
• PMID: 15038459 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Cholesterol, Dietary
• Enzyme Inhibitors
• Hypolipidemic Agents
• Indoles
• Linoleic Acids
• Lipids
• Lipoproteins, LDL
• N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide
• Polyunsaturated Alkamides
• Malondialdehyde
• Cholesterol
• Sterol O-Acyltransferase
• N-(2-methylbenzyl)linoleamide
• Propane

Topics

• Animals
• Antioxidants
• Arteriosclerosis (drug therapy)
• Body Weight (drug effects)
• Cholesterol (blood)
• Cholesterol, Dietary (pharmacology)
• Cricetinae
• Diet
• Enzyme Inhibitors (pharmacology)
• Hypolipidemic Agents
• Indoles (pharmacology)
• Linoleic Acids (metabolism)
• Lipid Metabolism
• Lipids (blood)
• Lipoproteins, LDL (metabolism)
• Liver (enzymology, metabolism)
• Male
• Malondialdehyde (metabolism)
• Mesocricetus
• Oxidation-Reduction
• Polyunsaturated Alkamides
• Propane (analogs & derivatives, pharmacology)
• Rabbits
• Sterol O-Acyltransferase (antagonists & inhibitors)