Abstract
2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / pharmacology
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Animals
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Cell Line, Tumor
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Combinatorial Chemistry Techniques
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Membranes, Artificial
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Mice
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Models, Molecular
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Nitriles / chemical synthesis*
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Nitriles / chemistry
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Nitriles / pharmacology
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Permeability
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PrPSc Proteins / antagonists & inhibitors*
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Solubility
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Structure-Activity Relationship
Substances
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Aminopyridines
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Membranes, Artificial
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Nitriles
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PrPSc Proteins