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.
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