Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

J Med Chem. 2018 Jul 12;61(13):5758-5764. doi: 10.1021/acs.jmedchem.8b00458. Epub 2018 Jun 22.

Abstract

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Catalytic Domain
  • Drug Design*
  • Epoxide Hydrolases / chemistry
  • Epoxide Hydrolases / metabolism
  • Hep G2 Cells
  • Humans
  • Mice
  • Molecular Docking Simulation
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism
  • Polypharmacology*
  • Tosyl Compounds / metabolism
  • Tosyl Compounds / pharmacology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • PPAR gamma
  • Tosyl Compounds
  • Epoxide Hydrolases
  • Ephx2 protein, mouse
  • zafirlukast