Abstract
(Hydroxyethyl)urea peptidomimetics are potent inhibitors of gamma-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4' revealed that the corresponding S2-S4' active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2'. A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid Precursor Protein Secretases
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Animals
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Binding Sites / drug effects
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Biomimetic Materials / chemical synthesis
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Biomimetic Materials / chemistry
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Biomimetic Materials / pharmacology*
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CHO Cells
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Cricetinae
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Endopeptidases / drug effects
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Endopeptidases / metabolism*
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Hydroxyurea / analogs & derivatives*
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Hydroxyurea / chemical synthesis
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Hydroxyurea / pharmacology*
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Molecular Structure
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Peptide Fragments / chemical synthesis
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Peptide Fragments / pharmacology*
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Peptide Fragments
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Protease Inhibitors
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Hydroxyurea