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.