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

• Published in: Journal of medicinal chemistry 2023-09, Vol.66 (17), p.11701-11717
• Main Authors: Mackman, Richard L., Kalla, Rao V., Babusis, Darius, Pitts, Jared, Barrett, Kimberly T., Chun, Kwon, Du Pont, Venice, Rodriguez, Lauren, Moshiri, Jasmine, Xu, Yili, Lee, Michael, Lee, Gary, Bleier, Blake, Nguyen, Anh-Quan, O’Keefe, B. Michael, Ambrosi, Andrea, Cook, Meredith, Yu, Joy, Dempah, Kassibla Elodie, Bunyan, Elaine, Riola, Nicholas C., Lu, Xianghan, Liu, Renmeng, Davie, Ashley, Hsiang, Tien-Ying, Dearing, Justin, Vermillion, Meghan, Gale, Michael, Niedziela-Majka, Anita, Feng, Joy Y., Hedskog, Charlotte, Bilello, John P., Subramanian, Raju, Cihlar, Tomas
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Chlorocebus aethiops; COVID-19; COVID-19 Drug Treatment; Furans; Humans; Nucleosides; Prodrugs - pharmacology; Prodrugs - therapeutic use; RNA, Viral; SARS-CoV-2
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00750

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-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 for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3–7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, 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 2, which supports development of 3 as a promising COVID-19 treatment.