Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys.

Remdesivir is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 () into lung cells, thereby forming the bioactive triphosphate . , an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for have prompted interest in oral approaches to generate . Here, we describe the discovery of a 5'-isobutyryl ester prodrug of (GS-5245, Obeldesivir, ) that has low cellular cytotoxicity and 3-7-fold improved oral delivery of in monkeys. Prodrug is cleaved presystemically to provide high systemic exposures of that overcome its less efficient metabolism to , leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to , which supports development of as a promising COVID-19 treatment.