PDF(Pubmed)
Abstract：
GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer\'s disease due to their involvement in the misfolding and accumulation of amyloid β (Aβ) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3β plays the most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive GSK-3β inhibitor (IC50 = 8 nM, Ki = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC50 = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound 62 effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility.
摘要：
GSK-3β,IKK-β,ROCK-1激酶与阿尔茨海默病的病理机制有关，因为它们参与了淀粉样β（Aβ）和tau蛋白的错误折叠和积累，以及炎症过程。在这些激酶中，GSK-3β起着最关键的作用。在这项研究中,我们介绍了化合物62，一种新颖的，非常有效，竞争性GSK-3β抑制剂(IC50=8nM,Ki=2nM），还表现出额外的ROCK-1抑制活性（IC50=2.3μM），并表现出抗炎和神经保护特性。在小胶质细胞BV-2细胞系的脂多糖诱导的炎症模型中,化合物62有效抑制一氧化氮(NO)和促炎细胞因子的产生。此外，它在冈田酸诱导的tau过度磷酸化的神经变性细胞模型中显示出神经保护作用。该化合物还显示出进一步开发的潜力，其特征在于其在小鼠微粒体中的化学和代谢稳定性以及良好的溶解度。
