Discovery of Novel Natural Product-Based PDE4 Inhibitors for Ischemic Stroke Treatment without Emetogenicity at Ultra-High Doses

Phosphodiesterase-4 (PDE4) inhibitors show potential for treating ischemic stroke, but are often constrained by emesis or low blood-brain barrier (BBB) permeability. To overcome these challenges, this paper developed novel PDE4 inhibitors via AI-driven structural evolution of natural antistroke products and identified the Phthalide derivative <b>B05</b> as a PDE4 inhibitor exhibiting excellent selectivity (selectivity index > 420), favorable pharmacological properties (<i>F</i> = 15.5%), and good BBB permeability. Significantly, B05 did not induce vomiting at ultrahigh doses (60 mg/kg), a significant advantage over conventional PDE4 inhibitors. <b>B05</b> protected neuronal cells from oxygen-glucose deprivation and reoxygenation-induced injury. Additionally, in the middle cerebral artery occlusion and reperfusion model, <b>B05</b> significantly reduced infarct volume, preserved BBB integrity, attenuated cerebral edema, inhibited astrocyte and microglial activation, prevented ischemia-induced neuronal apoptosis, and improved poststroke motor function and cognitive performance. These findings support the potential of <b>B05</b> as a promising candidate for the treatment of ischemic stroke.