Abstract
This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
MeSH terms
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Amines / chemical synthesis
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Amines / chemistry*
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Amines / pharmacology*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Cyclization
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Drug Design
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Models, Molecular
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Amines
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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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BACE1 protein, human