Xie Qiong, Zheng Zhaoxi, Shao Biyun, Fu Wei, Xia Zheng, Li Wei, Sun Jian, Zheng Wei, Zhang Weiwei, Sheng Wei, Zhang Qihong, Chen Hongzhuan, Wang Hao, Qiu Zhuibai
a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):659-671. doi: 10.1080/14756366.2016.1265521.
Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.
具有抗淀粉样蛋白生成特性的多功能氨基甲酸酯型乙酰胆碱酯酶（AChE）抑制剂，如苯丝氨酸，是治疗阿尔茨海默病（AD）的潜在药物。我们在此报告了使用药效团模型策略设计新的氨基甲酸酯，以调节胆碱酯酶和淀粉样蛋白生成。基于25种氨基甲酸酯型训练集化合物生成了一个具有五个特征的药效团模型。设计并合成了与该模型匹配良好的（-）-美普他酚氨基甲酸酯，其在体外试验中表现出纳摩尔级的AChE抑制活性和良好的抗淀粉样蛋白生成特性。苯基氨基甲酸酯43具有高效力（IC 31.6 nM）且对AChE具有轻微选择性，并且显示出低急性毒性。在酶动力学测定中，43表现出非竞争性抑制，并通过假不可逆机制反应。在50 μM浓度下，43在SH-SY5Y-APP细胞中还显示出优于苯丝氨酸（总Aβ降低31%）的淀粉样β蛋白（Aβ）降低效果（Aβ降低51.9%）。43对胆碱能和淀粉样蛋白生成途径的双重作用表明其作为对症治疗和疾病修饰药物的潜在用途。
