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

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.