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. 2025 Sep 13:300:118172.
doi: 10.1016/j.ejmech.2025.118172. Online ahead of print.

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

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

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

Tinghao Lu et al. Eur J Med Chem. .

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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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hongbin Zou reports financial support was provided by Zhejiang Provincial Natural Science Foundation of China. Hongbin Zou reports financial support was provided by National Natural Science Foundation of China. Hongbin Zou reports financial support was provided by Ministry of Science and Technology of the People's Republic of China. Peilin Yu reports financial support was provided by Ministry of Science and Technology of the People's Republic of China. Wei Yang reports financial support was provided by National Natural Science Foundation of China. Wei Yang reports financial support was provided by Zhejiang Provincial Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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