Discovery of imidazo[1,2-b]pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5113-8. doi: 10.1016/j.bmcl.2010.07.026. Epub 2010 Jul 13.

Abstract

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure-activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKbeta was constructed.

MeSH terms

  • Drug Discovery
  • I-kappa B Kinase / antagonists & inhibitors*
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • I-kappa B Kinase