Abstract
Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alzheimer Disease / drug therapy
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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 / analogs & derivatives*
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Aspartic Acid / chemical synthesis
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Aspartic Acid / chemistry
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Aspartic Acid / pharmacology
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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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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Dipeptides / chemical synthesis
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Drug Design
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Female
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Humans
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Mice
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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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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Dipeptides
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Sulfonamides
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Aspartic Acid
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leucyl-alanine
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse