학술논문
Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys
Document Type
Article
Author
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
Source
Journal of Medicinal Chemistry; September 2023, Vol. 66 Issue: 17 p11701-11717, 17p
Subject
Language
ISSN
00222623; 15204804
Abstract
Remdesivir 1is 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 1have 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 2in monkeys. Prodrug 3is cleaved presystemically to provide high systemic exposures of 2that 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 3as a promising COVID-19 treatment.