Pyrazoloheteroaryls: novel p38alpha MAP kinase inhibiting scaffolds with oral activity

Bioorg Med Chem Lett. 2006 Jan 15;16(2):262-6. doi: 10.1016/j.bmcl.2005.10.015. Epub 2005 Oct 24.

Abstract

A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis, Experimental / drug therapy*
  • Disease Models, Animal
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Molecular Structure
  • Pyrazines / administration & dosage*
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazoles / administration & dosage*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyridines / administration & dosage*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyrimidines / administration & dosage*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Pyrazines
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • pyrazolo(3,4-b)pyrazine
  • pyrazolo(3,4-b)pyridine
  • pyrazolo(3,4-d)pyrimidine
  • Mitogen-Activated Protein Kinase 14