INHIBITORS OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE - NOVEL TRISUBSTITUTED UREAS AS HYPOCHOLESTEROLEMIC AGENTS

Our continued interest in developing novel, potent acyl-CoA:cholestero l acyltransferase (ACAT) inhibitors, and our discovery of several acti ve series of disubstituted urea ACAT inhibitors, have led us to invest igate a series of trisubstituted ureas that are structural hybrids of our disubstituted series and of a trisubstituted urea ACAT inhibitor s eries disclosed by scientists at Lederle. This investigation has led t o the discovery of novel trisubstituted ureas, several of which inhibi t ACAT in the nanomolar range and effectively lower total plasma chole sterol when administered as a diet admixture in an acute model of hype rcholesterolemia in rats. One analogue (35) also lowered total cholest erol as efficaciously as CL 277,082 in our chronic hypercholesterolemi c rat model. The most notable finding of this study is that the SAR of the trisubstituted ureas diverges from that seen in our previously di sclosed disubstituted urea series. This series showed optimal activity with 2,4-difluoro and 2,4,6-trifluoro substitution on the urea N-phen yl, whereas the disubstituted series showed optimal activity with bulk y 2,6-disubstitution on the phenyl ring. (C) 1997 Elsevier Science Ltd .