Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects

Arch Pharm (Weinheim). 2014 Nov;347(11):798-805. doi: 10.1002/ardp.201400198. Epub 2014 Aug 27.

Abstract

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.

Keywords: Inhibitors; Rational drug design; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / toxicity
  • Biotransformation
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromans / chemical synthesis*
  • Chromans / metabolism
  • Chromans / pharmacology*
  • Chromans / toxicity
  • Drug Design*
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Indoles / toxicity
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

  • Anti-Inflammatory Agents
  • Chromans
  • Indoles
  • Receptors, Tumor Necrosis Factor, Type I
  • SPD-304
  • TNFRSF1A protein, human
  • Tumor Necrosis Factor-alpha