Abstract
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Aminopyridines / chemistry*
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Aminopyridines / pharmacokinetics
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Aminopyridines / therapeutic use
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Animals
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Binding Sites
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Central Nervous System / metabolism
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Computer Simulation
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Humans
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Mice
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Microsomes, Liver / metabolism
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Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 10 / metabolism
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Mitogen-Activated Protein Kinase 9 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 9 / metabolism
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Neurodegenerative Diseases / drug therapy*
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Neuroprotective Agents / chemistry*
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / therapeutic use
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Structure-Activity Relationship
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Triazines / chemistry*
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Triazines / pharmacokinetics
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Triazines / therapeutic use
Substances
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Aminopyridines
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Neuroprotective Agents
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Protein Kinase Inhibitors
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Triazines
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinase 9