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

AbstractRemdesivir1is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells thereby forming the bioactive triphosphate2-NTP.2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for1have prompted interest in oral approaches to generate2-NTP. Here we describe the discovery of a 5’-isobutyryl ester prodrug of2 (GS-5245, Obeldesivir,3) that has low cellular cytotoxicity and three to seven-fold improved oral delivery of2in monkeys. Prodrug3is cleaved pre-systemically to provide high systemic exposures of2that overcome its less efficient metabolism to2-NTPleading 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 to2which supports development of3as a promising COVID-19 treatment.