Five series of compounds (4-9) derived from N-(chlorocarbonyl) isocyanate have been synthesized and evaluated for their ability to inhibit the enzyme acyl-CoA:cholesterol O-acyltransferase and lower plasma cholesterol levels in cholesterol-fed rats. Structure-activity relationships indicate that the imino dicarboxylates (6 and 7) and the oxycarbonyl thiocarbamates (8) are the most potent and efficacious series. In these series, the combination of a 2,6-diisopropylphenyl group and an aliphatic alkyl group with a chain length between 6 and 14 carbon atoms gives good activity in vitro and in vivo. In addition, a hydrogen donor is required to maintain good in vitro activity, and the acidic proton on the central nitrogen in these series appears to be important for in vivo activity.