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

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 IKKß 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.

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

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