TY - JOUR
T1 - Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys
AU - Mackman, Richard L.
AU - Kalla, Rao V.
AU - Babusis, Darius
AU - Pitts, Jared
AU - Barrett, Kimberly T.
AU - Chun, Kwon
AU - Du Pont, Venice
AU - Rodriguez, Lauren
AU - Moshiri, Jasmine
AU - Xu, Yili
AU - Lee, Michael
AU - Lee, Gary
AU - Bleier, Blake
AU - Nguyen, Anh Quan
AU - O’Keefe, B. Michael
AU - Ambrosi, Andrea
AU - Cook, Meredith
AU - Yu, Joy
AU - Dempah, Kassibla Elodie
AU - Bunyan, Elaine
AU - Riola, Nicholas C.
AU - Lu, Xianghan
AU - Liu, Renmeng
AU - Davie, Ashley
AU - Hsiang, Tien Ying
AU - Dearing, Justin
AU - Vermillion, Meghan
AU - Gale, Michael
AU - Niedziela-Majka, Anita
AU - Feng, Joy Y.
AU - Hedskog, Charlotte
AU - Bilello, John P.
AU - Subramanian, Raju
AU - Cihlar, Tomas
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/9/14
Y1 - 2023/9/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.3c00750
DO - 10.1021/acs.jmedchem.3c00750
M3 - Article
C2 - 37596939
AN - SCOPUS:85169900800
SN - 0022-2623
VL - 66
SP - 11701
EP - 11717
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 17
ER -
