Design, Synthesis, and Structure-Activity Relationship Studies for a New Imidazole Series of J774 Macrophage Specific Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

Design, Synthesis, and Structure-Activity Relationship Studies for a New Imidazole Series of J774 Macrophage Specific Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which lead...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 38; no. 7; pp. 1067 - 1083
Main Authors: Maduskuie, Thomas P, Wilde, Richard G, Billheimer, Jeffrey T, Cromley, Debra A, Germain, Sandra, Gillies, Peter J, Higley, C. Anne, Johnson, Alex L, Pennev, Penio, Shimshick, Edward J, Wexler, Ruth R
Format: Journal Article
Language:English
Published: Washington, DC American Chemical Society 01-03-1995
Subjects:
Animals
Biological and medical sciences
Cell Line
Drug Design
General and cellular metabolism. Vitamins
Imidazoles - chemical synthesis
Imidazoles - pharmacology
Isoenzymes - antagonists & inhibitors
Macrophages - enzymology
Medical sciences
Mice
Microsomes, Liver - enzymology
Pharmacology. Drug treatments
Rats
Sterol O-Acyltransferase - antagonists & inhibitors
Structure-Activity Relationship
Acyltransferases
Imidazole derivatives
Rat
Enzyme
Transferases
Rodentia
Enzyme inhibitor
In vitro
Cholesterol
Vertebrata
Mammalia
Structure activity relation
Animal
Ureas
Fluorine Organic compounds
Chemical synthesis
Antilipemic agent
Macrophage
Sterol O-acyltransferase
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Summary:Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the development of fatty streaks. Inhibitors of the ACAT enzyme may retard this atherogenic process. We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay. This paper will describe the design, synthesis, and structure--activity relationship for this very potent series of compounds.
Bibliography:istex:AD5A07C725FBB22F7C144CB1A53ACB14F60FB886
ark:/67375/TPS-FHQ7Z9RF-0
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00007a004