Article
Author: Guo, Manyu ; Zhu, Zhihui ; Yao, Junchen ; Lu, Yingmei ; Zhu, Dongsheng ; Gu, Mengli ; Wang, Xuechun ; Zhang, Yanping ; Liu, Xiuxiu ; Xiang, Qiuping ; Chen, Jie ; Zhao, Chen ; Sun, Meiling ; Yao, Xinyi ; Hu, Mengdie ; Wang, Lin ; Wang, Zhen ; Zhang, Ying ; Cao, Qiaofeng ; Ma, Yuchen ; Niu, Le ; Han, Feng ; Wu, Jin
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.