Discovery of HZS60 as a Novel Brain Penetrant NMDAR/TRPM4 Interaction Interface Inhibitor with Improved Activity and Pharmacokinetic Properties for the Treatment of Cerebral Ischemia.

The death signaling complex comprising extrasynaptic NMDAR and TRPM4 plays a pivotal role in the pathogenesis of ischemic stroke. Targeting the protein-protein interactions between NMDAR and TRPM4 represents a promising therapeutic strategy for ischemic stroke. Herein, we describe the discovery of a novel series of NMDAR/TRPM4 interaction interface inhibitors aimed at enhancing neuroprotective efficacy and optimizing pharmacokinetic profiles. The representative compound HZS60 displayed significant neuroprotective effects against both NMDA and oxygen-glucose deprivation/reoxygenation-induced ischemic injury in primary neurons. Notably, HZS60 exhibited a favorable pharmacokinetic profile and excellent brain permeability. Furthermore, HZS60 provided effective neuroprotection following brain ischemia and reperfusion injury in vivo. Collectively, these findings underscore the potential of HZS60 as a promising candidate for the development of novel therapeutic strategies for ischemic stroke.