State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China.
Department of Toxicology, and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, P. R. China.
J Med Chem. 2021 Apr 8;64(7):3976-3996. doi: 10.1021/acs.jmedchem.0c02129. Epub 2021 Mar 30.
The transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer, and neurodegenerative diseases. However, the limit of specific inhibitors impedes the development of TRPM2-targeted therapeutic agents. To discover more potent and selective TRPM2 inhibitors, 59 -(-amylcinnamoyl) anthranilic acid (ACA) derivatives were synthesized and evaluated using calcium imaging and electrophysiology approaches. Systematic structure-activity relationship studies resulted in some potent compounds inhibiting the TRPM2 channel with sub-micromolar half-maximal inhibitory concentration values. Among them, the preferred compound exhibited TRPM2 selectivity over TRPM8 and TRPV1 channels as well as phospholipase A2 and showed neuroprotective activity in vitro. Following pharmacokinetic studies, was further evaluated in a transient middle cerebral artery occlusion model in vivo, which significantly reduced cerebral infarction. These data indicate that might serve as a useful tool for TRPM2-related research as well as a lead compound for the development of therapeutic agents for ischemic injury.
瞬时受体电位 melastatin 2（TRPM2）通道与缺血/再灌注损伤、炎症、癌症和神经退行性疾病有关。然而，特定抑制剂的局限性阻碍了 TRPM2 靶向治疗剂的发展。为了发现更有效和选择性的 TRPM2 抑制剂，我们合成了 59-（-戊基肉桂酰）邻氨基苯甲酸（ACA）衍生物，并使用钙成像和电生理学方法进行了评估。系统的构效关系研究产生了一些具有抑制 TRPM2 通道的活性化合物，其半数最大抑制浓度值在亚微摩尔范围内。其中，优选的化合物 对 TRPM8 和 TRPV1 通道以及磷脂酶 A2 具有选择性，并在体外显示出神经保护活性。在进行药代动力学研究后， 进一步在体内短暂性大脑中动脉闭塞模型中进行了评估，该模型显著减少了脑梗死。这些数据表明， 可能作为 TRPM2 相关研究的有用工具，以及开发缺血性损伤治疗剂的先导化合物。
