Abstract
Alzheimer's disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood-brain barrier. This work tests the hypothesis that the conjugation of peptidomimetic β-secretase inhibitors with a fragment of amyloid-β peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward β-secretase 1 in relation to β-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent's brains.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acylation
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Alzheimer Disease / drug therapy*
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / chemistry*
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Animals
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Brain / metabolism
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Caco-2 Cells
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Cell Survival / drug effects
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Drug Design
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Female
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Humans
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Male
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Mice
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptidomimetics / chemistry*
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Peptidomimetics / pharmacokinetics
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Peptidomimetics / pharmacology*
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Peptidomimetics / therapeutic use
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Rats
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Peptide Fragments
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Peptidomimetics
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Protease Inhibitors
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Amyloid Precursor Protein Secretases