Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4066-71. doi: 10.1016/j.bmcl.2011.04.121. Epub 2011 May 11.

Abstract

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Disease Models, Animal
  • Dogs
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Macaca fascicularis
  • Male
  • Molecular Structure
  • Pyridones
  • Pyrones / chemical synthesis*
  • Pyrones / chemistry
  • Pyrones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry
  • p38 Mitogen-Activated Protein Kinases / pharmacology

Substances

  • Benzamides
  • Enzyme Inhibitors
  • PH 797804
  • Pyridones
  • Pyrones
  • p38 Mitogen-Activated Protein Kinases