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Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-03-24 , DOI: 10.1016/j.ejmech.2020.112265
Zhipei Sang 1 , Keren Wang 1 , Ping Bai 2 , Anguo Wu 3 , Jian Shi 1 , Wenmin Liu 1 , Gaofeng Zhu 4 , Yiling Wang 3 , Yu Lan 5 , Zude Chen 5 , Yiyang Zhao 1 , Zhanpin Qiao 1 , Changning Wang 5 , Zhenghuai Tan 6
Affiliation  

A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ1-40. PET-CT imaging demonstrated that [11C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.



中文翻译:

设计,合成和生物学评价新型O-氨基甲酰基阿魏酰胺衍生物作为多靶点定向配体,用于治疗阿尔茨海默氏病

通过多目标定向配体(MTDLs)策略设计了一系列新的O-氨基甲酰基阿魏酰胺衍生物,合成并评估了这些衍生物用于治疗阿尔茨海默氏病(AD)。体外生物学评估表明,化合物4f是最佳的假不可逆h BChE(人丁酰胆碱酯酶)抑制剂,IC 50值为0.97μM4f是有效的选择性MAO-B(单胺氧化酶B)抑制剂(IC 50  = 5.3μM ),以及能抑制(58.2%)和集计(43.3%)的自介导的β聚集。4楼还可以降低病理性tau和APP清除水平,并且对LO2细胞显示出广泛的安全肝毒性。的体内研究显示,4F展示引人入胜的运动障碍恢复率和上的AlCl响应效率3介导的斑马鱼,并表现出显著保护作用引起的血管损伤β 1-40。PET-CT成像显示[ 11 C] 4f表现出较高的BBB渗透性(特别是可以到达海马体和大脑纹状体),静脉推注后脑吸收迅速。此外,化合物4f可以改善东pol碱引起的认知障碍。此外,还研究了4f的体外代谢,并显示了大鼠肝微粒体代谢中的3种代谢物,人肝微粒体中4种代谢物和大鼠肠道菌群中4种代谢物,为临床前研究提供了以前的数据。因此,这些结果表明化合物4f是一种先进的多功能药物,值得针对轻度服务的阿尔茨海默氏病进行进一步的临床前研究。

更新日期:2020-03-26
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