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 p otency evaluated against acyl-CoA: cholesterol acyltransferase (ACAT). Quan titative structure-activity relationship analysis revealed that their ACAT inhibitory activities were controlled by the hydrophobicity of the whole mo lecule, the substitution pattern of urea moiety. and the existence of carbo xylic acid. The derivatives with strong activities inhibited foam cell form ations. Moreover. these compounds showed antioxidative effects against low density lipoprotein (LDL). owing to their characteristic 3-tert-butyl-2-hyd roxy-5-methoxyphenyl substructure. Based on the mechanism of atherosclerosi s 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.