Abstract
beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism*
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Animals
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Biological Availability
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Brain / metabolism
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Dose-Response Relationship, Drug
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Isonicotinic Acids / chemical synthesis*
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Isonicotinic Acids / pharmacokinetics
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Isonicotinic Acids / pharmacology
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Mice
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Peptide Fragments / metabolism*
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Rats
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Structure-Activity Relationship
Substances
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Amides
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Amyloid beta-Peptides
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Isonicotinic Acids
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Peptide Fragments
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amyloid beta-protein (1-40)
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Amyloid Precursor Protein Secretases