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Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: Improvement of potency in vitro and in vivo

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
21
Issue
3
Identifiers
DOI: 10.1016/j.bmcl.2010.12.078
Keywords
  • Ikk
  • Nf-κB
  • Tnfα
  • Inhibitor
  • Interaction Model

Abstract

Graphical abstract We have increased the potency of imidazo[1,2- b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds such as 7c showed inhibitory activity of TNFα production in mice.

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