2. Academic Validation
  3. Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate

Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate

  • J Med Chem. 2021 May 13;64(9):5816-5837. doi: 10.1021/acs.jmedchem.0c02252.
Yang-Ming Zhang 1 2,  Hai-Yan Xu 1 3,  Hai-Ning Hu 1,  Fu-Yun Tian 1,  Fei Chen 1,  Hua-Nan Liu 1,  Li Zhan 1,  Xiao-Ping Pi 1,  Jie Liu 4,  Zhao-Bing Gao 1 3,  Fa-Jun Nan 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing City, Jiangsu 210023, China.
  • 4 Hainan Haiyao Company Ltd., No. 192, Nanhai Road, Xiuying District, Haikou City, Hainan 570311, China.
PMID: 33929863 DOI: 10.1021/acs.jmedchem.0c02252
Abstract

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.

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