Novel hydroxyphenylurea dual inhibitor against acyl-CoA: Cholesterol acyltransferase (ACAT) and low density lipoprotein (LDL) oxidation as antiatherosclerotic agent

Novel hydroxyphenylurea derivatives were synthesized and their inhibitory potency evaluated against acyl-CoA: cholesterol acyltransferase (ACAT). Quantitative structure-activity relationship analysis revealed that their ACAT inhibitory activities were controlled by the hydrophobicity of the whole molecule, the substitution pattern of urea moiety. and the existence of carboxylic acid. The derivatives with strong activities inhibited foam cell formations. Moreover. these compounds showed antioxidative effects against low density lipoprotein (LDL). owing to their characteristic 3-tert-butyl-2-hydroxy-5-methoxyphenyl substructure. Based on the mechanism of atherosclerosis generation, this hydroxyphenylurea-type dual inhibitor against both ACAT and LDL oxidation is expected to be a promising drug for atherosclerosis. (C) 2001 Elsevier Science Ltd. All rights reserved.