Yukimasa Azuma, Takashi Kawasaki, Kiyohito Ikemoto, Keisuke Obata, Katsutoshi
Ohno, Nobuko Sajiki, Toshihiro Yamada, Masahiro Yamasaki and Yoichi Nobuhara
Central Research Institute, Nissin Food Products Co., Ltd., 2247, Noji,
Kusatsu, Shiga, 525-0055, Japan
Abstract: 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.
Keywords: NTE-122, Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor,
Enzyme selectivity, Cholesterol-lowering effect