Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

• Published in: Journal of medicinal chemistry Vol. 37; no. 21; pp. 3511 - 3522
• Main Authors: Higley, C. Anne, Wilde, Richard G, Maduskuie, Thomas P, Johnson, Alexander L, Pennev, Pennio, Billheimer, Jeffrey T, Robinson, Candy S, Gillies, Peter J, Wexler, Ruth R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-10-1994
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Chemistry; Cholesterol - blood; Cricetinae; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Male; Mesocricetus; Microsomes, Liver - enzymology; Molecular Structure; Organic chemistry; Preparations and properties; Rats; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology; Acyltransferases; Imidazole derivatives; Five membered ring; Enzyme; Nitrogen heterocycle; Transferases; Rodentia; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Fluorine Organic compounds; Hamster; Antilipemic agent; Sterol O-acyltransferase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00047a009

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.