Discovery of Isobenzofuran-1(3H)-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(3H)-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, Cpd8l potently and selectively inhibited TREK-1 (IC₅₀ = 0.81 μM, selectivity >30 fold over other K⁺, Na⁺, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.