title: 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.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Nakamura
authors.forename: Shoji
authors.initials: S
authors.lastname: Kamiya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Akihisa
authors.initials: A
authors.lastname: Yoshimi
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Tarumi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kurahashi
mesh_terms: D000818:Animals; D000975:Antioxidants; D001161:Arteriosclerosis / Q000188:drug therapy; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology; D006224:Cricetinae; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000960:Hypolipidemic Agents; D007211:Indoles / Q000494:pharmacology*; D008041:Linoleic Acids / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008647:Mesocricetus; D010084:Oxidation-Reduction; D053284:Polyunsaturated Alkamides; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology*; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D007211:Indoles; D008041:Linoleic Acids; D008055:Lipids; D008077:Lipoproteins, LDL; C483406:N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide; D053284:Polyunsaturated Alkamides; D008315:Malondialdehyde; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C001757:N-(2-methylbenzyl)linoleamide; D011407:Propane