Abstract
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / enzymology
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Amyloid Precursor Protein Secretases
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Animals
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Aspartic Acid Endopeptidases
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Caprolactam / analogs & derivatives
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Caprolactam / chemistry*
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Cell Line
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Dogs
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Drug Design
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Drug Evaluation, Preclinical
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Endopeptidases / chemistry
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Endopeptidases / drug effects*
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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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Humans
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Molecular Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Succinates / chemistry*
Substances
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Enzyme Inhibitors
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Succinates
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Caprolactam
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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