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 B05 as a PDE4 inhibitor exhibiting excellent selectivity (selectivity
index > 420), favorable pharmacological properties (F = 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. B05 protected neuronal
cells from oxygen-glucose deprivation and reoxygenation-induced injury.
Additionally, in the middle cerebral artery occlusion and reperfusion
model, B05 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 B05 as a promising
candidate for the treatment of ischemic stroke.