作者: Mackman, Richard L. ; Kalla, Rao ; Babusis, Darius ; Pitts, Jared ; Barrett, Kimberly T. ; Chun, Kwon ; Pont, Venice Du ; 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, Elodie ; Bunyan, Elaine ; Riola, Nicholas C. ; Lu, Xianghan ; Liu, Renmeng ; Davie, Ashley ; Hsiang, Tien-Ying ; Gale, Michael Jr. ; Niedziela-Majka, Anita ; Feng, Joy Y. ; Hedskog, Charlotte ; Bilello, John P. ; Subramanian, Raju ; Cihlar, Tomas
Remdesivir 1 is an amidate 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 clin. 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 three to seven-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved pre-systemically 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 clin. 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.