Abstract
In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
MeSH terms
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Animals
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Cholesterol, LDL / biosynthesis
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Cholesterol, LDL / blood
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Cricetinae
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Guinea Pigs
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Heptanoic Acids / chemical synthesis*
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Heptanoic Acids / chemistry
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Heptanoic Acids / pharmacology
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Hypercholesterolemia / drug therapy*
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In Vitro Techniques
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Liver / drug effects*
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Liver / metabolism
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Male
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Mesocricetus
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Muscle Cells / drug effects
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Muscle Cells / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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7-(2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl)-3,5-dihydroxyheptanoic acid
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Cholesterol, LDL
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Pyrazoles