Substituted (1,2-Diarylethyl)amide Acyl-CoA:Cholesterol Acyltransferase Inhibitors: Effect of Polar Groups on in Vitro and in Vivo Activity

• Published in: Journal of medicinal chemistry 1995-05, Vol.38 (10), p.1600-1607
• Main Authors: Clader, John W, Berger, Joel G, Burrier, Robert E, Davis, Harry R, Domalski, Martin, Dugar, Sundeep, Kogan, Timothy P, Salisbury, Brian, Vaccaro, Wayne
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amides - pharmacology; Animals; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Cricetinae; General and cellular metabolism. Vitamins; Male; Medical sciences; Mesocricetus; Microsomes, Liver - enzymology; Pharmacology. Drug treatments; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00010a004

Substituted (1,2-diarylethyl)amides have been prepared and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster. Simple unsubstituted (diarylethyl)amides were potent inhibitors in vitro but showed poor activity in vivo. Introduction of polar groups at specific locations on the diarylethylamine moiety decreased in vitro activity but increased in vivo activity. Both effects were highly structure dependent, suggesting specific interactions which were mediating activity in each model. Optimization of these opposing effects led to compounds which were potent in both models.