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

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 seri...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-10, Vol.37 (21), p.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: Article
Language:English
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00047a009