Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Org Biomol Chem. 2013 Apr 7;11(13):2075-9. doi: 10.1039/c3ob27424a.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Olanzapine
  • Phosphodiesterase 4 Inhibitors / chemical synthesis*
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • Antipsychotic Agents
  • Phosphodiesterase 4 Inhibitors
  • Tumor Necrosis Factor-alpha
  • Benzodiazepines
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human
  • Olanzapine