Abstract
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Drug Discovery
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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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Hydantoins / chemical synthesis
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Hydantoins / chemistry*
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Hydantoins / pharmacology
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Hydrogen Bonding
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / pharmacology
Substances
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Enzyme Inhibitors
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Hydantoins
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Imidazoles
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Amyloid Precursor Protein Secretases