Abstract
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
MeSH terms
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Administration, Oral
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / drug effects
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Animals
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Aspartic Acid Endopeptidases
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Brain / drug effects
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Brain / metabolism
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Cyclohexanes / administration & dosage*
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology*
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Dose-Response Relationship, Drug
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Endopeptidases / drug effects*
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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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Mice
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Molecular Structure
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Peptide Fragments / drug effects
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Structure-Activity Relationship
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Sulfones / administration & dosage*
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Sulfones / chemistry
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Sulfones / pharmacology*
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Time Factors
Substances
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Amyloid beta-Peptides
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Cyclohexanes
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Enzyme Inhibitors
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Peptide Fragments
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Sulfones
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amyloid beta-protein (1-40)
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse