Tang Mei-Lin, Wen Zi-Hao, Wang Jing-Huan, Wang Mei-Ling, Zhang Heyanhao, Liu Xin-Hua, Jin Lin, Chang Jun
School of Pharmacy, Human Phenome Institute, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Department of Anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
ACS Med Chem Lett. 2022 Feb 21;13(3):436-442. doi: 10.1021/acsmedchemlett.1c00599. eCollection 2022 Mar 10.
Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A and A receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A/A 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/A AR antagonist) and preladenant (selective A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A/A AR antagonists. Among them, compound exerted excellent A/A AR binding affinity ( = 5.58/24.2 nM), an antagonistic effect (IC = 5.72/25.9 nM), and good metabolic stability in human liver microsomes, rat liver microsomes, and dog liver microsomes. Importantly, compound 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/A AR antagonists as a potential treatment for ischemic stroke.
缺血性中风是一种复杂的全身性疾病，其特征是高发病率、高致残率和高死亡率。突触前腺苷A1和A2A受体的激活可改变从兴奋性毒性到中风的多种脑损伤。因此，发现靶向A1/A2A双腺苷受体（AR）的治疗性化合物可能是治疗缺血性中风的一种策略。受两种临床III期药物ASP-5854（A1/A2A双AR拮抗剂）和普雷拉登特（选择性A2A AR拮抗剂）的启发，并采用混合药物策略，我们将新型吡啶酮取代的三唑并嘧啶支架表征为A1/A2A双AR拮抗剂。其中，化合物表现出优异的A1/A2A AR结合亲和力（Ki = 5.58/24.2 nM）、拮抗作用（IC50 = 5.72/25.9 nM），并且在人肝微粒体、大鼠肝微粒体和犬肝微粒体中具有良好的代谢稳定性。重要的是，化合物在氧-葡萄糖剥夺/再灌注（OGD/R）处理的HT22细胞模型中表现出剂量效应关系。这些发现支持将A1/A2A双AR拮抗剂开发为缺血性中风的潜在治疗方法。
