Abstract
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
MeSH terms
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Administration, Oral
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Alzheimer Disease / drug therapy
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Amyloid beta-Peptides / metabolism
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / metabolism
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Binding Sites
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Computer Simulation
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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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Mice
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacokinetics
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Rats
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Structure-Activity Relationship
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Thiazines / chemical synthesis
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Thiazines / chemistry*
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Thiazines / pharmacokinetics
Substances
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Amyloid beta-Peptides
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Ethylamines
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GSK188909
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Protease Inhibitors
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Thiazines
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Aspartic Acid Endopeptidases