Developing Intravenous Delivery of Water-Soluble Prodrugs of Idebenone for the Treatment of Acute Ischemic Stroke.

Ischemic stroke (IS) represents a substantial global health threat, but only a few effective medicines exist to treat IS, with a huge unmet clinical need. Idebenone (IDB), a coenzyme Q10 analogue, has multitarget effects, including enhancing mitochondrial energy metabolism, scavenging free radicals, and anti-inflammation, which is approved in Europe for treating Leber's hereditary optic neuropathy (LHON). However, IDB has poor water solubility and oral bioavailability, resulting in insufficient therapeutic plasma concentrations, even following high-dose oral administration, and limiting its use for brain diseases and acute-phase interventions. To address these challenges, we synthesized and identified novel water-soluble IDB prodrugs and found that compound I-7 could adopt intravenous delivery for treating acute IS (AIS) with excellent plasma and brain exposure in normal and IS rats. Besides, I-7 significantly alleviated brain infarct and edema and improved motor function and cerebral blood flow in acute and chronic IS rat models. Compound I-7 is currently undergoing comprehensive evaluation as a preclinical candidate for anti-AIS.