Sivaprakasam Prasanna, Han Xiaojun, Civiello Rita L, Jacutin-Porte Swanee, Kish Kevin, Pokross Matt, Lewis Hal A, Ahmed Nazia, Szapiel Nicolas, Newitt John A, Baldwin Eric T, Xiao Hong, Krause Carol M, Park Hyunsoo, Nophsker Michelle, Lippy Jonathan S, Burton Catherine R, Langley David R, Macor John E, Dubowchik Gene M
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2015 May 1;25(9):1856-63. doi: 10.1016/j.bmcl.2015.03.046. Epub 2015 Mar 24.
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
糖原合酶激酶-3（GSK-3）被认为在包括癌症、中风、双相情感障碍、糖尿病和神经退行性疾病在内的许多疾病的发病机制中起关键作用。在过去二十年中，GSK-3抑制一直是药物研究的主要领域。最近出现了大量关于GSK-3β选择性抑制剂及其共晶体结构的报道。我们从围绕吡咯并吡啶酮核心结构的连贯设计中鉴定出了几系列有前景的新型GSK-3β抑制剂。对中心间隔区周围化学空间的系统探索产生了强效的个位数和亚纳摩尔级GSK-3β抑制剂。在阿尔茨海默病（AD）转基因小鼠模型中口服给药时，一种示例性化合物在GSK-3磷酸化位点之一Ser396处显著降低了Tau磷酸化。X射线晶体学极大地有助于验证结合假说。
