Open AccessCholesterol-Lowering Effects of NTE-122, a Novel Acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitor, on Cholesterol Diet-Fed Rats and Rabbits
Author(s) -
Yukimasa Azuma,
Takashi Kawasaki,
Kiyohito Ikemoto,
Keisuke Obata,
Katsutoshi Ohno,
Nobuko Sajiki,
Toshihiro Yamada,
Masahiro Yamasaki,
Yoichi Nobuhara
Publication year - 1998
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.78.355
Subject(s) - sterol o acyltransferase , cholesterol , endocrinology , medicine , reverse cholesterol transport , chemistry , in vivo , acyltransferase , acyl coa , enzyme , biochemistry , biology , lipoprotein , microbiology and biotechnology
Pharmacological characterization of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was performed with both in vitro and in vivo assay systems. NTE-122 inhibited microsomal ACAT activities of various tissues (liver of rabbit and rat, small intestine of rabbit and rat, and aorta of rabbit) and cultured cells (HepG2 and CaCo-2), with IC50 values from 1.2 to 9.6 nM. The inhibition mode of NTE-122 was competitive for HepG2 ACAT. NTE-122 had no effect on other lipid metabolizing enzymes, such as 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA synthetase, cholesterol esterase, lecithin:cholesterol acyltransferase, acyl-CoA:sn-glycerol-3-phosphate acyltransferase and cholesterol 7alpha-hydroxylase up to 10 microM. When NTE-122 was administered to the cholesterol diet-fed rats, serum and liver cholesterol levels were markedly reduced with an ED50 of 0.12 and 0.44 mg/kg/day, respectively. In the cholesterol diet-fed rabbits, NTE-122 significantly lowered plasma and liver cholesterol levels at more than 2 mg/kg/day. These results indicate that NTE-122 is a potent, selective and competitive inhibitor of ACAT, making it a worth while therapeutic agent for hypercholesterolemia and atherosclerosis.