Indolizine Derivatives Inhibit TRPM2 and Protect against Ischemic Brain Injury with an Extended Treatment Window

  • J Med Chem. 2025 Apr 10;68(7):7642-7661. doi: 10.1021/acs.jmedchem.5c00186.
Tinghao Lu  1 ,  Yi Zhang  2 ,  Jinbiao Li  1 ,  MeiJie Dai  1  3 ,  Huan Liu  2  4 ,  Huajian Zhu  1 ,  Shaozi Fu  2  5 ,  Xianhao Dong  1 ,  Fenghao Sun  6 ,  Hongwei Lin  2  7 ,  Xiangnan Zhang  1  8 ,  Wei Yang  2  4 ,  Peilin Yu  2  9 ,  Hongbin Zou  1
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
  • 2. Zhejiang University School of Medicine, Hangzhou 310058, PR China.
  • 3. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou 310058, PR China.
  • 4. Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR China.
  • 5. Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
  • 6. Zhongshan hospital, Fudan University, Shanghai 200000, PR China.
  • 7. Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
  • 8. Institute of Pharmacology and Toxicology, State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 9. Department of Toxicology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR China.
PMID: 40168472 DOI: 10.1021/acs.jmedchem.5c00186
Abstract

Ischemic stroke, a major cause of disability and death worldwide, lacks effective treatments due to the complexity of brain ischemia/reperfusion (I/R) injury. The transient receptor potential melastatin 2 (TRPM2) channel is a promising therapeutic target. In this study, an extracellular TRPM2 inhibitor A1 with an indolizine scaffold was identified through chemical library screening. Four series of indolizine derivatives were synthesized, yielding four compounds with TRPM2 inhibitory activity comparable to or superior to A1, as confirmed by calcium fluorescence and electrophysiological assays. These compounds demonstrated significant neuroprotective effects in vitro. Among them, D10 showed robust efficacy in reducing cerebral infarction in a transient middle cerebral artery occlusion (tMCAO) model, surpassing edaravone. When administered 24 h postreperfusion and continued for 7 days, D10 exhibited sustained in vivo antistroke activity and improved survival rates compared to edaravone and vehicle controls. D10 represents a promising lead compound for ischemic stroke therapy.

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