ACYL COA-CHOLESTEROL ACYLTRANSFERASE (ACAT) INHIBITORS - SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF A NEW SERIES OF TRISUBSTITUTED IMIDAZOLES

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been syn thesized and demonstrated to be potent inhibitors of acyl-CoA:choleste rol acyltransferase (ACAT). The design, synthesis, and structure-activ ity relationships for this series are reported herein. One of the comp ounds from this series, -diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptyl urea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vi vo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.