Abstract
Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones.
MeSH terms
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Animals
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Cell Death / drug effects
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Cerebellum / cytology
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Imidazoles
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Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
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Neurons / cytology
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Neurons / drug effects
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / pharmacology
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Phosphorylation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-jun / metabolism
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Imidazoles
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Neuroprotective Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-jun
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Mitogen-Activated Protein Kinase 10
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p38 Mitogen-Activated Protein Kinases