Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer's Disease
Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer's Disease
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二苯基共轭咪唑衍生物作为潜在谷氨酰胺酰环化酶抑制剂治疗阿尔茨海默病的合成和评价
DOI：
10.1021/acs.jmedchem.7b00648
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发表时间：
2017-08-10
影响因子：
7.3
通讯作者：
Wu, Haiqiang
中科院分区：
文献类型：
--
作者：
Li, Manman;Dong, Yao;Wu, Haiqiang
谷氨酰环化酶（QC）的高表达通过催化焦谷氨酸（pE）修饰的β -淀粉样蛋白（A β）肽的产生，有助于阿尔茨海默病（AD）的开始。通过QC抑制pE-A β 5的产生已被认为是一种治疗AD的新方法。本研究合理设计并合成了一系列二苯基共轭咪唑衍生物。该支架的类似物表现出对人QC （hQC）的有效抑制活性，并具有良好的体外血脑屏障（BBB）渗透性。进一步的评估证实，所选择的hQC抑制剂28抑制hQC的活性，显著减少pE-A β s在培养细胞和体内的产生，并改善AD小鼠的行为。
High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer's disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified beta-amyloid (A beta) peptides. Preventing the generation of pE-A beta s by QC inhibition has been suggested as a novel approach to a disease-modifying therapy for AD. In this work, a series of diphenyl conjugated imidazole derivatives (DPCIs) was rationally designed and synthesized. Analogues with this scaffold exhibited potent inhibitory activity against human QC (hQC) and good in vitro blood brain barrier (BBB) permeability. Further assessments corroborated that the selected hQC inhibitor 28 inhibits the activity of hQC, dramatically reduces the generation of pE-A beta s in cultured cells and in vivo, and improves the behavior of AD mice.