Structure-activity relationships of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N '-(3,4-dimethylphenyl)piperazine and analogues as inhibitors of acyl-CoA: Cholesterol O-acyltransferase

A novel series of acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors were synthesized from a lead compound, 1-(4-hydroxy-3-methoxyphenyl)-7-phe nylhept-1-en-3-one (1, Yakuchinone B) through a modification of three regio ns (A, B, C) in the molecule, In this study, the compounds prepared were te sted for in vitro inhibitory activity on microsomal ACAT from the liver of rats and for in vivo hypocholesterolemic activity in rats given a high chol esterol diet, N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylpheny l)piperazine (45), which belongs to the amide compounds, has finally been d iscovered. Compound 45 inhibited rat hepatic ACAT in a more striking manner than Cl-976, an amide compound ACAT inhibitor, and it exhibited a high lev el of hypocholesterolemic activity in vivo. Since 45 strongly inhibited bot h microsomal ACAT prepared from HepG2 (a cell line derived from human hepat ocarcinoma) and Caco2 (a cell line derived from human colon adenocarcinoma) , there is speculation that 45 might have the ability to inhibit ACAT in bo th the human intestine and liver independent of the difference in the distr ibution of ACAT isozymes, On the other hand, 45 did not induce adrenotoxici ty in subacute toxicity studies in rats. These results suggest that it has promise for development as a new therapeutic agent for hypercholesterolemia and atherosclerosis.