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 <b>A1</b> 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 <b>A1</b>, as confirmed by calcium fluorescence and electrophysiological assays. These compounds demonstrated significant neuroprotective effects <i>in vitro</i>. Among them, <b>D10</b> 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, <b>D10</b> exhibited sustained <i>in vivo</i> antistroke activity and improved survival rates compared to edaravone and vehicle controls. <b>D10</b> represents a promising lead compound for ischemic stroke therapy.
Authors
- Fenghao Sun (ORCID: https://orcid.org/0000-0003-0210-5204)
- Wei Yang (ORCID: https://orcid.org/0000-0003-3065-1843)
- Xiangnan Zhang (ORCID: https://orcid.org/0000-0002-7603-7403)
- Peilin Yu (ORCID: https://orcid.org/0000-0002-8230-4061)
- Huan Liu (ORCID: https://orcid.org/0000-0003-0749-9118)
- Hongbin Zou (ORCID: https://orcid.org/0000-0001-6784-2737)
- Huajian Zhu (ORCID: https://orcid.org/0000-0002-6786-8811)
- Shaozi Fu (ORCID: https://orcid.org/0000-0001-8262-536X)
- Xiang Dong (ORCID: https://orcid.org/0000-0001-6356-1647)
- Jinbiao Li (ORCID: https://orcid.org/0000-0001-5884-9574)
- Hongwei Lin (ORCID: https://orcid.org/0000-0003-2525-8174)
- Yi Zhang (ORCID: https://orcid.org/0000-0001-7321-1202)
- Mingzu Dai
- Tinghao Lu
Institutions
- Fudan University (CN)
- Sir Run Run Shaw Hospital (CN)
- Zhongshan Hospital (CN)
- Pharmaceutical Biotechnology (Czechia) (CZ)
- Institute of Pharmacology (CZ)
- Zhejiang University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00186
- Citations
- 5
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 5.59
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology
- Natural Science Foundation of Zhejiang Province