Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase‑3 Inhibitors

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer’s disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.糖原合酶激酶3（GSK-3）是一种丝氨酸/苏氨酸激酶，拥有众多底物蛋白。其中多数底物参与调控多种细胞功能，涵盖代谢、分化、增殖与细胞凋亡等过程。抑制GSK-3或可用于治疗阿尔茨海默病（Alzheimer’s disease, AD）、2型糖尿病、情绪障碍及部分癌症等多种疾病，但该治疗策略面临诸多重大挑战。本文报道了一类强效且激酶选择性极高的异烟酰胺类GSK-3抑制剂，该类化合物的成员在阿尔茨海默病三转基因小鼠模型中展现出口服活性。这类化合物极高的激酶选择性与简便的合成路线，使其具备作为工具化合物与治疗药物开展进一步研究的良好前景。