Discovery of orally bioavailable phenyltetrazolium derivatives for the acute treatment and the secondary prevention of ischemic stroke.

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. [Display omitted] • A series of novel phenyltetrazolium derivatives were designed and synthesized. • Among 18 synthesized compounds, compound B4 exhibited strongest cell protective potency and oral exposure. • Compound B4 inhibited stroke both in tMCAO model and PT model. [ABSTRACT FROM AUTHOR]