Abstract
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / antagonists & inhibitors*
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Animals
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Drug Design*
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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 / pharmacology*
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Inhibitory Concentration 50
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Mice
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Mice, Inbred Strains
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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APP protein, human
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Enzyme Inhibitors
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Heterocyclic Compounds, 3-Ring
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Sulfonamides
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Amyloid Precursor Protein Secretases