DESIGN, SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF NOVEL 4,4-BIS(TRIFLUOROMETHYL)IMIDAZOLINES AS ACYL-COA - CHOLESTEROL ACYLTRANSFERASE (ACAT) INHIBITORS AND ANTIHYPERCHOLESTEROLEMIC AGENTS

Novel 4,4-bis(trifluoromethyl)imidazolines have been found to be the p otent acyl-CoA cholesterol acyltransferase (ACAT) inhibitors. ACAT is responsible for cholesterol esterification in the intestine, liver, an d the arterial wall. These novel imidazolines also inhibit cholesterol ester formation in the macrophage. Several compounds have shown poten t serum cholesterol-lowering activity in several animal models. Para-s ubstitution of the 2-phenyl is critical for in vitro and in vivo activ ity. The 4,4-bis(trifluoromethyl)imidazolines with a para-cyano group on 2-phenyl and a 4-alkylcyclohexyl amide as the side-chain at the 5-p osition possess the most potent inhibitory activity in this series. Ba sed on biochemical studies, this series acts as a competitive inhibito r with respect to cholesterol binding at the enzyme, which distinguish es it from most of the ACAT inhibitors discovered to date. Preliminary biological studies supported by X-ray crystal structures, molecular m odeling, and structure-activity relationship (SAR) studies suggest tha t this series may be a cholesterol mimic. (C) 1997 The DuPont Merck Ph armaceutical Company. Published by Elsevier Science Ltd.