Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer’s Disease Drug Discovery,ACS Medicinal Chemistry Letters

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Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer’s Disease Drug Discovery
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-02-09 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00463
Xue-Yang Jiang ₁ , Ting-Kai Chen ₁ , Jun-Ting Zhou ₁ , Si-Yu He , Hong-Yu Yang , Yao Chen ₂ , Wei Qu ₁ , Feng Feng ₁ , Hao-Peng Sun

Affiliation

Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer’s disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase (hAChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC₅₀ = 6.5 nM) and hGSK-3β kinase activity (IC₅₀ = 66 nM). It also showed good inhibitory effect on β-amyloid self-aggregation (inhibitory rate = 46%) at 20 μM. Western blot analysis revealed that compound 2f inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed that 2f significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3β and AChE pathway dual inhibition as a promising strategy for AD treatment.

中文翻译：

双重GSK-3β/ AChE抑制剂作为多靶点抗阿尔茨海默氏病药物发现的新策略

设计多靶标定向配体（MTDL）被认为是解决诸如阿尔茨海默氏病（AD）等复杂和多因素疾病的一种有前途的方法。同时抑制两个关键的AD靶标，糖原合酶激酶3β（GSK-3β）和人乙酰胆碱酯酶（h AChE），可能代表着对临床疗效的突破。因此，设计并合成了新型的GSK-3β/ AChE双靶标抑制剂家族。在这些混合动力车，2F显示出最有希望的轮廓二者上的纳摩尔抑制剂ħ乙酰胆碱酯酶（IC ₅₀ = 6.5纳米）和ħ GSK-3β激酶活性（IC ₅₀= 66 nM）。在20μM时，它对β淀粉样蛋白自聚集也显示出良好的抑制作用（抑制率= 46％）。蛋白质印迹分析表明，化合物2f抑制了小鼠神经母细胞瘤N2a-Tau细胞中tau蛋白的过度磷酸化。体内研究证实2f可以显着改善东pol碱治疗的ICR小鼠的认知障碍，其肝毒性比他克林低。这项研究为评估GSK-3β和AChE途径双重抑制提供了新的线索，作为AD治疗的一种有前途的策略。

更新日期：2018-02-09

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