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

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.