Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor

Bioorg Med Chem Lett. 2002 Jun 17;12(12):1559-62. doi: 10.1016/s0960-894x(02)00238-x.

Abstract

Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis / drug therapy
  • Cytokines / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Urea / analogs & derivatives
  • Urea / chemical synthesis*
  • Urea / chemistry
  • Urea / pharmacology*
  • Urea / therapeutic use
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Cytokines
  • Enzyme Inhibitors
  • N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea
  • Urea
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases