Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors

Bioorg Med Chem Lett. 2008 Apr 15;18(8):2739-44. doi: 10.1016/j.bmcl.2008.02.067. Epub 2008 Mar 4.

Abstract

A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.

MeSH terms

  • Amides / chemistry
  • Animals
  • Crystallography, X-Ray
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemistry*
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Amides
  • Protein Kinase Inhibitors
  • Pyrroles
  • Triazines
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinase 14