Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties

Bioorg Med Chem Lett. 2008 Jan 1;18(1):179-83. doi: 10.1016/j.bmcl.2007.10.106. Epub 2007 Nov 1.

Abstract

Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / metabolism
  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Edema / drug therapy
  • ErbB Receptors / metabolism
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Benzimidazoles
  • Imidazoles
  • Peptide Fragments
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 14