Abstract
We have identified small-molecule dibenzazepine inhibitors of beta-secretase (BACE1). These BACE1 inhibitors possess two key salient features. The first is a seven-membered heterocyclic ring fused to two aromatic rings representing the P3-P2 residues. The second is an amide and/or amide bioisostere representing the P1' residue. Rational optimization led to the identification of potent analogues, such as 10 (K(I) = 211 nM).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemistry
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Dibenzazepines / chemical synthesis*
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Dibenzazepines / chemistry
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Dibenzazepines / pharmacology*
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Drug Design*
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Imidazoles / chemistry
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Inhibitory Concentration 50
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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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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Amides
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Dibenzazepines
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Imidazoles
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Phthalic Acids
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Protease Inhibitors
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isophthalate
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imidazole
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Amyloid Precursor Protein Secretases
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dibenzazepine