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

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

  • Eur J Med Chem. 2024 Jun 1:275:116542. doi: 10.1016/j.ejmech.2024.116542.
Yang Lu 1,  Haoran Lin 2,  Yaping Xu 3,  Zexu Shen 2,  Yu Guo 3,  Yizhen Jin 3,  Qiuqiu Shi 3,  Haifeng Chen 3,  Yuxin Zhuang 3,  Wenhai Huang 4,  Jinxin Che 5,  Haibin Dai 6,  Xiaowu Dong 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 3 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 4 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Hangzhou Medical College, Hangzhou, 310013, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
  • 6 Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address: haibindai@zju.edu.cn.
  • 7 Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. Electronic address: dongxw@zju.edu.cn.
PMID: 38875807 DOI: 10.1016/j.ejmech.2024.116542
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.

Keywords

Neuroprotection; Pharmacokinetic property; Phenyltetrazolium; Secondary prevention of stroke.

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