Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4633-7. doi: 10.1016/j.bmcl.2011.05.091. Epub 2011 May 30.

Abstract

Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Arthritis / drug therapy
  • Binding Sites
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Mice
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Pyrroles / chemistry*
  • Rats
  • Structure-Activity Relationship
  • Triazines / chemistry*
  • Triazines / pharmacology
  • Triazines / therapeutic use

Substances

  • Anti-Inflammatory Agents
  • Protein Kinase Inhibitors
  • Pyrroles
  • Triazines
  • Mitogen-Activated Protein Kinase 14