Discovery of Pyridone-Substituted Triazolopyrimidine Dual A 2A /A 1 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 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.