Abstract
The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.
MeSH terms
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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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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Aspartic Acid Endopeptidases / metabolism
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CHO Cells
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Humans
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptide Fragments / chemistry*
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Peptide Fragments / pharmacology
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology
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Protein Structure, Secondary / physiology
Substances
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Macrocyclic Compounds
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Peptide Fragments
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Protease Inhibitors
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human