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

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Discovery of 2-Ethoxy-5-isobutyramido-N-1-substituted Benzamide Derivatives as Selective Kv2.1 Inhibitors with In Vivo Neuroprotective Effects
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-27 , 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

Affiliation

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.

中文翻译：

发现 2-乙氧基-5-异丁酰胺-N-1-取代的苯甲酰胺衍生物作为具有体内神经保护作用的选择性 Kv2.1 抑制剂

Kv2.1参与调节神经元兴奋性和神经元细胞凋亡，抑制Kv2.1是预防缺血性中风细胞死亡并实现神经保护的潜在策略。在这项工作中，设计并合成了一系列新型苯甲酰胺衍生物作为Kv2.1抑制剂，广泛的构效关系导致了高效、选择性的Kv2.1抑制剂，其IC ₅₀值为10 ^–8 M。 80 （IC ₅₀ = 0.07 μM，选择性是其他 K ⁺ 、Na ⁺和 Ca ²⁺离子通道的 130 倍以上）能够减少 H ₂ O ₂诱导的 HEK293/Kv2.1 细胞凋亡。此外，它的抗缺血功效得到了证实，因为它显着减少了 MCAO 大鼠模型中的梗塞体积。此外，化合物80具有适当的血浆 PK 参数。它可以作为研究Kv2.1病理功能的探针，值得进一步探索。

更新日期：2023-12-27

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