Abstract
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.
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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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hydrogen Bonding
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Imidazolidines / chemical synthesis*
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Imidazolidines / chemistry
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Imidazolidines / pharmacology*
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Models, Molecular
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Molecular Structure
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology*
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Imidazolidines
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Piperidines
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Amyloid Precursor Protein Secretases