2. Academic Validation
  3. Discovery of 2-Ethoxy-5-isobutyramido- N-1-substituted Benzamide Derivatives as Selective Kv2.1 Inhibitors with In Vivo Neuroprotective Effects

Discovery of 2-Ethoxy-5-isobutyramido- N-1-substituted Benzamide Derivatives as Selective Kv2.1 Inhibitors with In Vivo Neuroprotective Effects

  • J Med Chem. 2024 Jan 11;67(1):213-233. doi: 10.1021/acs.jmedchem.3c01245.
Jie Zhou 1,  Weiping Wang 2,  Dong Liu 1,  Shaofeng Xu 2,  Xue Wang 1,  Xinyuan Zhang 3,  Xiaoyu Wang 1,  Yan Li 4,  Li Sheng 4,  Xiaoliang Wang 2,  Bailing Xu 1
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 Information Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 38150670 DOI: 10.1021/acs.jmedchem.3c01245
Abstract

Kv2.1 is involved in regulating neuronal excitability and neuronal cell Apoptosis, and inhibiting Kv2.1 is a potential strategy to prevent cell death and achieve neuroprotection in ischemic stroke. In this work, a series of novel benzamide derivatives were designed and synthesized as Kv2.1 inhibitors, and extensive structure-activity relationships led to highly potent and selective Kv2.1 inhibitors having IC50 values of 10-8 M. Among them, compound 80 (IC50 = 0.07 μM, selectivity >130 fold over other K+, Na+, and Ca2+ ion channels) was able to decrease the Apoptosis of HEK293/Kv2.1 cells induced by H2O2. Furthermore, its anti-ischemic efficacy was demonstrated as it markedly reduced the infarct volume in MCAO rat model. Additionally, compound 80 possessed appropriate plasma PK parameters. It could serve as a probe to investigate Kv2.1 pathological functions and deserved to be further explored.

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