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

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-13 DOI:10.1016/j.ejmech.2025.118172

Tinghao Lu , MeiJie Dai , Kaiyue Ying , Xianhao Dong , Wanglin Qu , Peichen Pan , Wei Yang , Xiangnan Zhang , Peilin Yu , Hongbin Zou

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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.

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金刚烷基衍生物作为有效和选择性TRPM2抑制剂的发现，显著降低了hERG的责任

缺血性中风仍然是世界范围内死亡的主要原因。瞬时受体电位美拉他汀2 （TRPM2）是一种参与缺血-再灌注损伤的钙渗透通道，已成为一个有希望的靶点。我们之前报道了一种有效的TRPM2抑制剂D10，但随后的人醚-à-go-go-related基因（hERG）抑制实验显示，对这两个通道的微摩尔活性相当，表明安全窗口很窄。hERG安全性的进一步战略优化导致了LC4的开发，其特点是新安装了adamantyl基团。综合表征，包括钙成像、电生理和药代动力学研究，表明LC4表现出增强的TRPM2抑制作用，降低hERG负性，保留选择性，改善代谢稳定性。在短暂性大脑中动脉闭塞（tMCAO）模型中，LC4显著降低梗死面积和氧化应激水平。这些结果表明LC4可能是治疗缺血性卒中的有希望的临床前候选药物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.