Abstract
A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Abeta40 production in N2a cells stably transfected with Swedish human APP.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / biosynthesis
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Amyloid beta-Protein Precursor / genetics
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Binding Sites
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Cell Line
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Computer Simulation
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Drug Design
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Humans
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Ligands
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Models, Molecular*
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacology
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Transfection
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Ligands
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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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BACE2 protein, human
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BACE1 protein, human