Cholesterol-lowering effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol diet-fed rats and rabbits.

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.

• Authors: Y Azuma, T Kawasaki, K Ikemoto, K Obata, K Ohno, N Sajiki, T Yamada, M Yamasaki, Y Nobuhara
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 78 Issue 3 Pg. 355-64 (Nov 1998) ISSN: 0021-5198 [Print] Japan
• PMID: 9869270 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Cholesterol, Dietary
• Cyclohexanes
• Enzyme Inhibitors
• NTE 122
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Cholesterol
• Hydroxymethylglutaryl CoA Reductases
• Cholesterol 7-alpha-Hydroxylase
• Acyltransferases
• Sterol O-Acyltransferase
• Phosphatidylcholine-Sterol O-Acyltransferase
• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• Sterol Esterase
• Coenzyme A Ligases
• FAA2 protein, S cerevisiae
• long-chain-fatty-acid-CoA ligase

Topics

• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• Acyltransferases (drug effects, metabolism)
• Aniline Compounds (chemistry, pharmacology)
• Animals
• Caco-2 Cells
• Cholesterol (metabolism)
• Cholesterol 7-alpha-Hydroxylase (drug effects, metabolism)
• Cholesterol, Dietary (administration & dosage)
• Coenzyme A Ligases (drug effects, metabolism)
• Cyclohexanes (chemistry, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Hydroxymethylglutaryl CoA Reductases (drug effects, metabolism)
• Male
• Phosphatidylcholine-Sterol O-Acyltransferase (drug effects, metabolism)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Sterol Esterase (drug effects, metabolism)
• Sterol O-Acyltransferase (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured