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 were prepared by the stepwise addition of nitrogen, oxygen, and sulfur nucleophiles to N-chlorosulfonyl isocyanate. The (aminosulfonyl)ureas 3−44 were the most potent inhibitors in vitro, with several compounds having IC50 values < 1 μM. Although the other series of compounds were not as potent in vitro, many compounds did display good in vivo activity in cholesterol-fed rats. Several of the oxysulfonyl carbamates (including CI-999, 115) showed excellent lipid-lowering activity in the chronic in vivo screen, demonstrating significant cholesterol lowering in a pre-established hypercholesterolemic state.