Li Manman, Dong Yao, Yu Xi, Li Yue, Zou Yongdong, Zheng Yizhi, He Zhendan, Liu Zhigang, Quan Junmin, Bu Xianzhang, Wu Haiqiang
Department of Pharmacy, School of Medicine, Shenzhen University , Shenzhen 518060, China.
College of Life Sciences and Oceanography, Shenzhen University , Shenzhen 518060, China.
J Med Chem. 2017 Aug 10;60(15):6664-6677. doi: 10.1021/acs.jmedchem.7b00648. Epub 2017 Jul 25.
High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer's disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ) peptides. Preventing the generation of pE-Aβs 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-Aβs in cultured cells and in vivo, and improves the behavior of AD mice.
谷氨酰胺环化酶（QC）的高表达通过催化产生神经毒性焦谷氨酸（pE）修饰的β-淀粉样蛋白（Aβ）肽，促进阿尔茨海默病（AD）的发病。通过抑制QC来阻止pE-Aβ的产生，已被认为是一种治疗AD的疾病修饰新方法。在这项工作中，我们合理设计并合成了一系列二苯基共轭咪唑衍生物（DPCIs）。具有这种骨架的类似物对人QC（hQC）表现出强大的抑制活性，并具有良好的体外血脑屏障（BBB）通透性。进一步评估证实，所选的hQC抑制剂28可抑制hQC的活性，显著减少培养细胞和体内pE-Aβ的产生，并改善AD小鼠的行为。
