Abstract
Modulation of γ-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived γ-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of γ-secretase modulators.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Acids / chemical synthesis
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Acids / chemistry
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Alzheimer Disease / drug therapy
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / drug effects
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Amyloid beta-Protein Precursor / drug effects
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / analysis
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Carbazoles / analysis
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Carbazoles / chemical synthesis*
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Carbazoles / chemistry
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Carbazoles / pharmacology
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Carboxylic Acids / analysis
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology
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Cell Line
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Cell Proliferation / drug effects
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Fenofibrate / analogs & derivatives
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Fenofibrate / chemistry
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Humans
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Mice
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Molecular Targeted Therapy
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Structure-Activity Relationship
Substances
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APP protein, human
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Acids
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Anti-Inflammatory Agents, Non-Steroidal
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Carbazoles
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Carboxylic Acids
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Amyloid Precursor Protein Secretases
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Fenofibrate