Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 3: exploration of effective compounds in arthritis models

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4550-5. doi: 10.1016/j.bmcl.2011.05.115. Epub 2011 Jun 6.

Abstract

We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis, Experimental / drug therapy*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Imidazoles / chemistry*
  • Mice
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridazines / therapeutic use
  • Rats
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • Tumor Necrosis Factor-alpha
  • imidazole
  • I-kappa B Kinase