新型肉桂酰胺-哌啶和哌嗪衍生物的设计、合成及神经保护作用

Jia-Yi Li, Xin-Yan Peng, Yi-Lei Huang, Ling Jiang, Jian-Qi Li, Xue-Zhi Yang, Qing-Wei Zhang
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引用次数: 0

摘要

在我们之前的研究中,Fenazinel显示出良好的神经保护作用;然而,当Fenazinel进入1期临床试验时,它与某些副作用有关。本研究旨在探索高效低毒的新型神经保护剂。有证据表明,肉桂酸及其类似物可能是治疗中风的有希望的先导化合物。本研究首次合成了一系列具有潜在神经保护作用的Fenazinel衍生物,其中肉桂酸及其类似物为关键官能基。采用甲基噻唑四氮唑试验评估谷氨酸诱导的SH-SY5Y细胞神经毒性中化合物的神经保护作用。通过hERG结合试验评估药物引起的QT间期延长或其他心脏毒性。通过小鼠缺氧条件下的存活时间和大脑中动脉闭塞模型,检测最强效化合物在体内的神经保护活性。我们的数据表明,在这些衍生物中,化合物9d在体外表现出与测试浓度下的芬那嗪相当的有效神经保护活性。值得注意的是,9d在体内耐缺氧和MCAO模型中均表现出较弱的hERG抑制活性。综上所述,9d具有治疗中风的潜力,可以被认为是进一步开发的主要神经保护剂。
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Design, Synthesis, and Neuroprotective Effects of Novel Cinnamamide-Piperidine and Piperazine Derivatives
In our previous studies, Fenazinel has shown good neuroprotective effects; however, when Fenazinel entered phase 1 clinical trials, it was associated with certain side effects. This study aimed to explore novel neuroprotective agents with higher potency and lower toxicity. Evidence suggested that cinnamic acid and its analogs may serve as promising lead compounds for stroke treatment. In this study, a series of Fenazinel derivatives were first synthesized with potential neuroprotective effects with fragments including cinnamic acid and its analogs as key functional groups. The methyl thiazolyl tetrazolium assay was performed to assess the neuroprotective effects of the compounds in glutamate-induced neurotoxicity in SH-SY5Y cells. The hERG binding assay was conducted to assess drug-induced QT prolongation or other cardiotoxicity. The neuroprotective activity of the most potent compound in vivo was tested through the survival time of mice under the hypoxic condition and a middle cerebral artery occlusion model. Our data suggested that among those derivatives, compound 9d exhibited potent neuroprotective activity in vitro comparable to Fenazinel at the test concentrations. Significantly, 9d exhibited weak hERG inhibitory activity, showing moderate activities in both hypoxia-tolerant and MCAO models in vivo. Given the above, 9d has the potential for the treatment of stroke and could be considered a lead neuroprotective agent for further development.
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