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

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.