Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate
Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate
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DOI：
10.1021/acs.jmedchem.0c02252
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发表时间：
2021-04-30
影响因子：
7.3
通讯作者：
Nan, Fa-Jun
中科院分区：
文献类型：
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作者：
Zhang, Yang-Ming;Xu, Hai-Yan;Nan, Fa-Jun
我们以前报道，P-瑞替加滨（P-RTG），一个瑞替加滨（RTG）类似物轴承炔丙基基团的氮原子在连接的RTG，显示中度抗惊厥疗效。最近，我们的进一步努力导致了HN 37（pynegabine）的发现，其在删除邻位-NH 2基团并将两个相邻的甲基基团安装到氨基甲酸酯基序上时表现出令人满意的化学稳定性。HN 37在一系列临床前癫痫发作模型中表现出对神经元Kv 7通道增强的激活效力和高体内功效，包括最大电休克试验和6 Hz的药物抗性边缘癫痫发作模型。HN 37化学稳定性提高，疗效强，安全性好，已进入中国癫痫治疗临床试验阶段。
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 HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo 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, HN37 has progressed to clinical trial in China for epilepsy treatment.