Discovery of imidazo(1,2-b)pyridazines as IKKbeta inhibitors. Part 2: improvement of potency in vitro and in vivo.

摘要

We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKbeta 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 IKKbeta by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds showed inhibitory activity of TNFalpha production in mice.