Structure-activity relationship of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl)propoxy] phenyl]-N'-pentylurea and analogues. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity.

摘要: We have discovered N-butyl-N'-[2-(dimethylamino)-6-[3-(4-phenyl-1H- imidazol-1-yl)propoxy]phenyl]urea (4), a novel, potent, and systemically bioavailable inhibitor of ACAT (acylCoA:cholesterol O-acyltransferase). The structure-activity relationships (SARs) this lead compound 4 were investigated by systematic modification four regions in the molecule. compounds prepared study tested for vitro inhibitory activity toward both aortic intestinal ACATs, selected further vivo hypocholesterolemic activity. studies not only resulted discovery N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl) propoxy]phenyl]-N'-pentylurea (24), with potent moderate plasma level after oral administration, but also revealed SAR each modified region. Four (4, 13, 14, 24) testing antiatherosclerotic activity; 4, 24 reduced atherosclerotic plaque development to 38-45% control value terms area, while 14 did significant effect.