Novel Hybrids of Optically Active Ring-Opened 3-n-Butylphthalide Derivative and Isosorbide as Potential Anti-Ischemic Stroke Agents

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• 作者：Xiaoli Wang ; Linna Wang ; Tingting Li ; Zhangjian Huang ; Yisheng Lai ; Hui Ji ; Xiaolong Wan ; Jinyi Xu ; Jide Tian ; Yihua Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3078-3089
• 全文大小：513K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

In search of novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of hybrids ((S)- and (R)-5a鈥?b>f) from optically active ring-opened NBP derivative and isosorbide were synthesized for evaluating their anti-ischemic stroke activity. Compound (S)-5e displayed the strongest activity in inhibiting the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, with 10.0- and 8.4-fold more effectiveness than (S)-NBP, respectively. Furthermore, (S)-5e was stable in artificial gastrointestinal fluids and could penetrate the blood鈥揵rain barrier (BBB) with an appreciate lipid/water partition coefficient relative to (S)-NBP. More importantly, oral treatment with (S)-5e protected from acute thrombosis and inhibited the ischemia/reperfusion-related brain injury in animals. Our findings suggest that (S)-5e may be promising for further evaluation for the intervention of ischemic stroke.