Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4059-65. doi: 10.1016/j.bmcl.2011.04.120. Epub 2011 May 13.

Abstract

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Microsomes, Liver / enzymology
  • Molecular Structure
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Pyridazines
  • Pyridones
  • Pyrimidines
  • p38 Mitogen-Activated Protein Kinases
  • VX-745