Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, No. 39, Science and Technology Avenue, High-Tech Industrial Development Zone, Yantai City, Shandong 264000, China.
J Med Chem. 2021 May 13;64(9):5816-5837. doi: 10.1021/acs.jmedchem.0c02252. Epub 2021 Apr 30.
We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH group and installing two adjacent methyl groups to the carbamate motif. exhibited enhanced activation potency toward neuronal Kv7 channels and high efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, has progressed to clinical trial in China for epilepsy treatment.
我们之前报道过，具有炔丙基取代基的培利加滨（P-RTG）是利加滨（RTG）连接子中氮原子上的 RTG 类似物，具有中等的抗惊厥作用。最近，我们的进一步努力导致了发现了（pynegabine），它通过删除邻位的 -NH 基团并在碳酸酯基序上安装两个相邻的甲基基团，显示出令人满意的化学稳定性。与 RTG 相比， 对神经元 Kv7 通道的激活能力增强，在一系列临床前癫痫模型中具有高效性，包括最大电休克试验和 6 Hz 型抗药性边缘性癫痫发作模型。由于其化学稳定性得到改善、疗效更强、安全性更好， 已在中国进入癫痫治疗的临床试验。
