Abstract
A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacology*
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Benzodiazepines / chemical synthesis
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Dose-Response Relationship, Drug
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Drug Design*
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Humans
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Olanzapine
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Phosphodiesterase 4 Inhibitors / chemical synthesis*
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Phosphodiesterase 4 Inhibitors / chemistry
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Phosphodiesterase 4 Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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Antipsychotic Agents
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Phosphodiesterase 4 Inhibitors
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Tumor Necrosis Factor-alpha
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Benzodiazepines
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, human
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Olanzapine