Design, Structure–Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-<i>b</i>]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors
Richard A. Hartz, Vijay T. Ahuja, Prasanna Sivaprakasam, Hong Xiao, Carol Krause, Wendy Clarke, Kevin Kish, H.A. Lewis, Nicolas Szapiel, R. Ramu, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R. Burton, John E. Macor, Gene M. Dubowchik
Abstract
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-3β 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-3β inhibitors are described herein. Structure–activity relationship studies led to the identification of potent GSK-3β 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-3β inhibitor that significantly lowered levels of phosphorylated tau.