Discovery of Pyridone-Substituted Triazolopyrimidine Dual A(2A)/A(1) AR Antagonists for the Treatment of Ischemic Stroke

[Image: see text] Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A(2A) and A(1) receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A(2A)/A(1) 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)/A(1) 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)/A(1) AR antagonists. Among them, compound 1a exerted excellent A(2A)/A(1) AR binding affinity (K(i) = 5.58/24.2 nM), an antagonistic effect (IC(50) = 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)/A(1) AR antagonists as a potential treatment for ischemic stroke.