Abstract
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
MeSH terms
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Animals
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Atorvastatin
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Combinatorial Chemistry Techniques
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Disease Models, Animal
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Fluorobenzenes / pharmacology
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Hepatocytes / drug effects
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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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Mice
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Molecular Structure
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Muscle Cells / drug effects*
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Rosuvastatin Calcium
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology*
Substances
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Fluorobenzenes
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Pyrimidines
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Pyrroles
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Sulfonamides
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Rosuvastatin Calcium
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Atorvastatin