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

  • J Med Chem. 2025 Jan 23;68(2):2008-2043. doi: 10.1021/acs.jmedchem.4c02772.
Meiling Sun  1  2 ,  Lin Wang  3 ,  Qiaofeng Cao  3 ,  Xuechun Wang  3 ,  Ying Zhang  3 ,  Manyu Guo  3 ,  Jie Chen  1  2 ,  Yuchen Ma  3 ,  Le Niu  3 ,  Yanping Zhang  3 ,  Mengdie Hu  3 ,  Mengli Gu  3 ,  Zhihui Zhu  3 ,  Xinyi Yao  3 ,  Junchen Yao  3 ,  Chen Zhao  3 ,  Jin Wu  1  2 ,  Xiuxiu Liu  3 ,  Yingmei Lu  1  2 ,  Zhen Wang  4 ,  Qiuping Xiang  5 ,  Feng Han  3  6 ,  Dongsheng Zhu  1  3
Affiliations
  • 1. Department of Neurology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China.
  • 2. School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 3. Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai 200032, China.
  • 5. Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo No.2 Hospital, Ningbo 315000, China.
  • 6. The affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian 223300, China.
PMID: 39745498 DOI: 10.1021/acs.jmedchem.4c02772
Abstract

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.

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