Discovery of Isobenzofuran-1(3<i>H</i>)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects

TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3<i>H</i>)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure-activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC₅₀ values of a low micromolar level. Among them, <b>Cpd8l</b> potently and selectively inhibited TREK-1 (IC₅₀ = 0.81 μM, selectivity >30 fold over other K⁺, Na⁺, and TRP channels). <b>Cpd8l</b> remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, <b>Cpd8l</b> could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that <b>Cpd8l</b> may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.