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

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKβ inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKβ inhibitory activity and TNFα 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 IKKβ was constructed.

Graphical abstractWe developed the HTS-hit imidazo[1,2-b]pyridazine derivatives and acquired some potent compounds such as 8e. These compounds showed potent IKKβ inhibitory activity and high kinase selectivity. The structure–activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compound with IKKβ was constructed.Figure optionsDownload full-size imageDownload as PowerPoint slide