Abstract
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Protein Precursor / antagonists & inhibitors
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Combinatorial Chemistry Techniques*
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Crystallography, X-Ray
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Ethylamines / chemical synthesis*
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Ethylamines / chemistry
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Ethylamines / pharmacology*
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Humans
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Molecular Structure
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amyloid beta-Protein Precursor
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Ethylamines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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ethylamine