SUBSTITUTED (1,2-DIARYLETHYL)AMIDE ACYL-COA-CHOLESTEROL ACYLTRANSFERASE INHIBITORS - EFFECT OF POLAR GROUPS ON IN-VITRO AND IN-VIVO ACTIVITY

Substituted (1,2-diarylethyl)amides have been prepared and evaluated f or their ability to inhibit microsomal acyl-CoA:cholesterol acyltransf erase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster. Simple unsubstituted (diaryleth yl)amides were potent inhibitors in vitro but showed poor activity in vivo. Introduction of polar groups at specific locations on the diaryl ethylamine moiety decreased in vitro activity but increased in vivo ac tivity. Both effects were highly structure dependent, suggesting speci fic interactions which were mediating activity in each model. Optimiza tion of these opposing effects led to compounds which were potent in b oth models.