Abstract
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases / chemistry*
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Dipeptides / chemistry*
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Drug Design
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Endopeptidases
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Ethylenes / chemical synthesis*
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Ethylenes / chemistry
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Humans
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Models, Molecular
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Molecular Mimicry
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Phthalic Acids / chemical synthesis*
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Phthalic Acids / chemistry
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Structure-Activity Relationship
Substances
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Amides
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Dipeptides
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Ethylenes
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N-(1-(3,5-difluorobenzyl)-2-hydroxy-4-isobutylcarbamoylpentyl)-N',N'-dipropylisophthalamide
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Phthalic Acids
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Protease Inhibitors
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hydroxyethylene
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human