Abstract
Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / chemistry
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Acetamides / pharmacokinetics*
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Acetamides / pharmacology*
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Acetanilides / chemistry
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Acyl Coenzyme A / antagonists & inhibitors*
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Administration, Oral
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Animals
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Anticholesteremic Agents / chemical synthesis
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Anticholesteremic Agents / chemistry
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Anticholesteremic Agents / pharmacokinetics
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Anticholesteremic Agents / pharmacology*
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Apolipoproteins / metabolism
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Atherosclerosis / metabolism*
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry
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Benzopyrans / pharmacokinetics*
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Benzopyrans / pharmacology*
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Cholesterol / metabolism
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Coumarins / chemistry
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Dose-Response Relationship, Drug
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Drug Discovery
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Targeted Therapy
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Structure-Activity Relationship
Substances
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2-(7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl)-N-(4-chloro-2-(trifluoromethyl)phenyl)acetamide
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Acetamides
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Acetanilides
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Acyl Coenzyme A
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Anticholesteremic Agents
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Apolipoproteins
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Benzopyrans
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Coumarins
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Enzyme Inhibitors
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4-phenylcoumarin
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Cholesterol
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acetanilide