INHIBITORS OF ACYL-COA-CHOLESTEROL O-ACYLTRANSFERASE .17. STRUCTURE-ACTIVITY-RELATIONSHIPS OF SEVERAL SERIES OF COMPOUNDS DERIVED FROM N-CHLOROSULFONYL ISOCYANATE

Several series of acyl-CoA:cholesterol O-acyltransferase inhibitors we re prepared by the stepwise addition of nitrogen, oxygen, and sulfur n ucleophiles to N-chlorosulfonyl isocyanate. The (aminosulfonyl)ureas 3 -44 were the most potent inhibitors in vitro, with several compounds h aving IC50 values < 1 mu M. Although the other series of compounds wer e not as potent in vitro, many compounds did display good in vivo acti vity in cholesterol-fed rats. Several of the oxysulfonyl carbamates (i ncluding CI-999, 115) showed excellent lipid-lowering activity in the chronic in vivo screen, demonstrating significant cholesterol lowering in a pre-established hypercholesterolemic state.