The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3′-isobutyryl ester 5a, the 5′-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.

remdesivir 的核苷代谢物 GS-441524 显示出强大的抗 SARS-CoV-2 功效，并且正在临床上作为 COVID-19 的口服抗病毒药物进行评估。然而，该核苷在非人灵长类动物中的口服生物利用度较差，可能影响其治疗效果。在此，我们报道了多种在碱基或糖部分进行修饰的 GS-441524 类似物，以及一些前药形式，包括五种异丁酰酯、两种l-缬氨酸酯和一种氨基甲酸酯。在新核苷中，只有 7-氟类似物3c具有中等抗 SARS-CoV-2 活性，其氨基磷酸酯前药7在 Vero E6 细胞中表现出降低的活性。至于前药，3'-异丁酰酯5a、5'-异丁酰酯5c和三异丁酰酯5g氢溴酸盐在小鼠体内表现出优异的口服生物利用度（F = 71.6%、86.6% 和 98.7%），这为 GS-441524 的药代动力学优化提供了很好的见解.