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

Pharmacological characterization of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3- (4-dimethyl-amino phenyl)ureido]methyl] cyclohexane), a novel acyl-CoA: cho lesterol 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 ra t, and aorta of rabbit) and cultured cells (HepG2 and CaCo-2), with IC50 va lues 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, suc h as 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA synthetase, cholest erol esterase, lecithin:cholesterol acyltransferase, acyl-CoA:sn-glycerol-3 -phosphate acyltransferase and cholesterol 7 alpha-hydroxylase up to 10 mu M. When NTE-122 was administered to the cholesterol diet-fed rats, serum an d 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 s ignificantly lowered plasma and liver cholesterol levels at more than 2 mg/ kg/day. These results indicate that NTE-122 is a potent, selective and comp etitive inhibitor of ACAT, making it a worth while therapeutic agent for hy percholesterolemia and atherosclerosis.