Abstract：
The potential for secondary stroke prevention, which can significantly reduce the risk of recurrent strokes by almost 90%, underscores its critical importance. N-butylphthalide (NBP) has emerged as a promising treatment for acute cerebral ischemia, yet its efficacy for secondary stroke prevention is hindered by inadequate pharmacokinetic properties. This study, driven by a comprehensive structural analysis, the iterative process of structure optimization culminated in the identification of compound B4, which demonstrated exceptional neuroprotective efficacy and remarkable oral exposure and oral bioavailability. Notably, in an in vivo transient middle cerebral artery occlusion (tMCAO) model, B4 substantially attenuated infarct volumes, surpassing the effectiveness of NBP. While oral treatment with B4 exhibited stronger prevention potency than NBP in photothrombotic (PT) model. In summary, compound B4, with its impressive oral bioavailability and potent neuroprotective effects, offers promise for both acute ischemic stroke treatment and secondary stroke prevention.
摘要：
二级预防中风的潜力，这可以显着降低近90％的复发性中风的风险，强调其至关重要性。丁苯酞（NBP）已成为急性脑缺血的有希望的治疗方法，然而，其用于二级预防中风的功效受到药物代谢动力学特性不足的阻碍。这项研究,在全面的结构分析的推动下，结构优化的迭代过程最终导致化合物B4的鉴定,其表现出优异的神经保护功效和显著的口服暴露和口服生物利用度。值得注意的是,在体内短暂性大脑中动脉闭塞（tMCAO）模型中，B4实质上减轻了梗死体积，超越NBP的有效性。而在光血栓形成(PT)模型中,用B4口服治疗表现出比NBP更强的预防效力。总之,化合物B4具有令人印象深刻的口服生物利用度和有效的神经保护作用，为急性缺血性卒中治疗和二级卒中预防提供了希望。
