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

Abstract

Remdesivir <b>1</b> is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (<b>2</b>) into lung cells, thereby forming the bioactive triphosphate <b>2-NTP</b>. <b>2-NTP</b>, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for <b>1</b> have prompted interest in oral approaches to generate <b>2-NTP</b>. Here, we describe the discovery of a 5'-isobutyryl ester prodrug of <b>2</b> (GS-5245, Obeldesivir, <b>3</b>) that has low cellular cytotoxicity and 3-7-fold improved oral delivery of <b>2</b> in monkeys. Prodrug <b>3</b> is cleaved presystemically to provide high systemic exposures of <b>2</b> that overcome its less efficient metabolism to <b>2-NTP</b>, 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 <b>2</b>, which supports development of <b>3</b> as a promising COVID-19 treatment.