Abstract
A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.
MeSH terms
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Animals
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Cell Line
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Crystallography, X-Ray
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Enzyme Activation / drug effects
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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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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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JNK Mitogen-Activated Protein Kinases / chemistry
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Male
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Models, Molecular
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Molecular Structure
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Rats
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Rats, Wistar
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Isoquinolines
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JNK Mitogen-Activated Protein Kinases
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isoquinoline