Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2

Bioorg Med Chem. 2021 Sep 15:46:116364. doi: 10.1016/j.bmc.2021.116364. Epub 2021 Aug 11.

Abstract

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.

Keywords: Antiviral; Covid-19; GS-441524; Isobutyrate; Nucleoside; Prodrug; SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacokinetics
  • Adenosine / pharmacology
  • Adenosine / toxicity
  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / toxicity
  • Chlorocebus aethiops
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Prodrugs / toxicity
  • SARS-CoV-2 / drug effects*
  • Vero Cells

Substances

  • Antiviral Agents
  • Prodrugs
  • GS-441524
  • Adenosine