Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors

Glycogen synthase kinase-3 (GSK-3) is a serine/ threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3 beta has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3 beta inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3 beta inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3 beta inhibitor that significantly lowered levels of phosphorylated tau.