SAR of 2,6-diamino-3,5-difluoropyridinyl substituted heterocycles as novel p38MAP kinase inhibitors

Bioorg Med Chem Lett. 2002 Aug 19;12(16):2109-12. doi: 10.1016/s0960-894x(02)00336-0.

Abstract

2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / pathology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Structure
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Pyridones / therapeutic use
  • Rats
  • Structure-Activity Relationship*
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Pyridones
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases