A Near-Infrared Photoactivatable, Brain-Penetrant Prodrug of the Prolyl Hydroxylase Inhibitor Vadadustat for Neuroprotection in Ischemic Stroke.

Ischemic stroke is a leading cause of mortality and disability with limited therapeutic options. Activation of the hypoxia-inducible factor (HIF) pathway via knockout of the neuronal prolyl hydroxylase domain (PHD) enzyme has shown neuroprotective potential. However, most PHD inhibitors exhibit poor brain penetration due to their high intrinsic polarity, particularly the presence of carboxyl groups. Here, we reported a near-infrared (NIR)-activated photocaged prodrug (11) that masks the acidic pharmacophore of Vadadustat (5) to facilitate BBB penetration and enable spatiotemporally controlled drug release in the brain upon NIR irradiation. Prodrug 11 significantly attenuated cellular injury in HT22 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) following NIR irradiation. Moreover, in a mouse model of cerebral ischemia-reperfusion (I/R), prodrug 11 reduced infarct volume and brain edema, and promoted neurological recovery. These findings highlight a photoactivatable, brain-penetrant prodrug strategy for spatiotemporally controlled neuroprotection.