Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors
Richard A. Hartz, Vijay T. Ahuja, Guanglin Luo, Ling Chen, Prasanna Sivaprakasam, Hong Xiao, Carol Krause, Wendy Clarke, Songmei Xu, John S. Tokarski, 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 serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer’s disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer’s disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer’s disease model.