Discovery of Pyridone-Substituted Triazolopyrimidine Dual A2A/A1 AR Antagonists for the Treatment of Ischemic Stroke

Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A_2A and A₁ receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A_2A/A₁ adenosine receptor (AR)-targeting therapeutic compounds could be a strategy for the treatment of ischemic stroke. Inspired by two clinical phase III drugs, ASP-5854 (dual A_2A/A₁ AR antagonist) and preladenant (selective A_2A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A_2A/A₁ AR antagonists. Among them, compound 1a exerted excellent A_2A/A₁ AR binding affinity (K_i = 5.58/24.2 nM), an antagonistic effect (IC₅₀ = 5.72/25.9 nM), and good metabolic stability in human liver microsomes, rat liver microsomes, and dog liver microsomes. Importantly, compound 1a demonstrated a dose–effect relationship in the oxygen-glucose deprivation/reperfusion (OGD/R)-treated HT22 cell model. These findings support the development of dual A_2A/A₁ AR antagonists as a potential treatment for ischemic stroke.