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

• Published in: ACS medicinal chemistry letters 2022-03, Vol.13 (3), p.436-442
• Main Authors: Tang, Mei-Lin, Wen, Zi-Hao, Wang, Jing-Huan, Wang, Mei-Ling, Zhang, Heyanhao, Liu, Xin-Hua, Jin, Lin, Chang, Jun
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.1c00599

Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A2A and A1 receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A2A/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 A2A/A1 AR antagonist) and preladenant (selective A2A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A2A/A1 AR antagonists. Among them, compound 1a exerted excellent A2A/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 A2A/A1 AR antagonists as a potential treatment for ischemic stroke.