Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

Glycogen synthase kinase-3 (GSK-3) is a serine/threoninekinasethat serves as an important regulator of a broad range of cellularfunctions. It has been linked to Alzheimer's disease as wellas various other diseases, including mood disorders, type 2 diabetes,and cancer. There is considerable evidence indicating that GSK-3 beta in the central nervous system plays a role in the production of abnormal,hyperphosphorylated, microtubule-associated tau protein found in neurofibrillarytangles associated with Alzheimer's disease. A series of analoguescontaining a pyrimidine-based hinge-binding heterocycle was synthesizedand evaluated, leading to the identification of highly potent GSK-3inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compoundsare orally bioavailable, brain-penetrant GSK-3 inhibitors that loweredlevels of phosphorylated tau in a triple-transgenic mouse Alzheimer'sdisease model.

Automated summary

Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cellular functions, implicated in diseases such as Alzheimer's disease, mood disorders, diabetes, and cancer. Its role in the production of abnormal tau protein in neurofibrillary tangles associated with Alzheimer's disease has been established. The synthesis and evaluation of pyrimidine-based GSK-3 inhibitors led to the identification of highly potent compounds that effectively lowered phosphorylated tau levels in a mouse model of Alzheimer's disease.