Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity

Bioorg Med Chem Lett. 2001 Nov 5;11(21):2867-70. doi: 10.1016/s0960-894x(01)00570-4.

Abstract

Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole inhibitors of p38 kinase is reported. Oral administration of inhibitors possessing a cyclohexan-4-ol or piperidin-4-yl group at N-1 in combination with alkoxy, amino(alkyl), phenoxy and anilino substitution at the 2-position of the pyrimidine was found to potently inhibit LPS-induced TNF in mice and rats. The selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580.

MeSH terms

  • Administration, Oral
  • Animals
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Lipoxygenase / drug effects
  • Liver / enzymology
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Pyrimidines / chemistry*
  • Rats
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Imidazoles
  • Pyrimidines
  • Lipoxygenase
  • Prostaglandin-Endoperoxide Synthases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases