2. Academic Validation
  3. Discovery of adamantyl derivatives as potent and selective TRPM2 inhibitors with significantly reduced hERG liability

Discovery of adamantyl derivatives as potent and selective TRPM2 inhibitors with significantly reduced hERG liability

  • Eur J Med Chem. 2025 Dec 15:300:118172. doi: 10.1016/j.ejmech.2025.118172.
Tinghao Lu 1,  MeiJie Dai 2,  Kaiyue Ying 3,  Xianhao Dong 1,  Wanglin Qu 1,  Peichen Pan 1,  Wei Yang 4,  Xiangnan Zhang 5,  Peilin Yu 6,  Hongbin Zou 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 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.
  • 3 Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
  • 4 Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
  • 5 Institute of Pharmacology and Toxicology, State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 6 Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Department of Toxicology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
  • 7 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: zouhb@zju.edu.cn.
PMID: 40961584 DOI: 10.1016/j.ejmech.2025.118172
Abstract

Ischemic stroke remains a leading cause of mortality worldwide. Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable channel involved in ischemia-reperfusion injury, has emerged as a promising target. We previously reported an effective TRPM2 inhibitor D10, but subsequent human ether-à-go-go-related gene (hERG) inhibition assays revealed comparable micromolar activity against both channels, indicating a narrow safety window. Further strategic optimization of the hERG safety profile led to the development of LC4, featuring a newly installed adamantyl group. Comprehensive characterization, including calcium imaging, electrophysiological, and pharmacokinetic studies, demonstrated that LC4 exhibited enhanced TRPM2 inhibition, reduced hERG liability, retained selectivity, and improved metabolic stability. In a transient middle cerebral artery occlusion (tMCAO) model, LC4 reduced the infarct volume and oxidative-stress level significantly. These results suggest that LC4 could be a promising preclinical candidate for treatment of ischemic stroke.

Keywords

Adamantyl; Ischemic stroke; TRPM2 inhibitor; hERG liability; tMCAO model.

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