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

  • J Med Chem. 2023 Sep 14;66(17):11701-11717. doi: 10.1021/acs.jmedchem.3c00750.
Richard L Mackman  1 ,  Rao V Kalla  1 ,  Darius Babusis  2 ,  Jared Pitts  3 ,  Kimberly T Barrett  4 ,  Kwon Chun  1 ,  Venice Du Pont  3 ,  Lauren Rodriguez  5 ,  Jasmine Moshiri  5 ,  Yili Xu  6 ,  Michael Lee  7 ,  Gary Lee  7 ,  Blake Bleier  4 ,  Anh-Quan Nguyen  4 ,  B Michael O'Keefe  8 ,  Andrea Ambrosi  8 ,  Meredith Cook  8 ,  Joy Yu  8 ,  Kassibla Elodie Dempah  9 ,  Elaine Bunyan  9 ,  Nicholas C Riola  3 ,  Xianghan Lu  3 ,  Renmeng Liu  2 ,  Ashley Davie  2 ,  Tien-Ying Hsiang  10 ,  Justin Dearing  11 ,  Meghan Vermillion  11 ,  Michael Gale Jr  10 ,  Anita Niedziela-Majka  7 ,  Joy Y Feng  6 ,  Charlotte Hedskog  5 ,  John P Bilello  3 ,  Raju Subramanian  2 ,  Tomas Cihlar  3
Affiliations
  • 1. Medicinal Chemistry, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 2. Drug Metabolism, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 3. Discovery Virology, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 4. Formulation and Process Development, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 5. Clinical Virology, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 6. Biochemistry, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 7. Biology, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 8. Process Chemistry, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 9. Process Development, Gilead Sciences Incorporated, 333 Lakeside Drive, Foster City, California 94404 United States.
  • 10. Center for Innate Immunity and Immune Disease, Department of Immunology, School of Medicine, University of Washington, Seattle, Washington 98109 United States.
  • 11. Lovelace Biomedical Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, New Mexico 87108 United States.
PMID: 37596939 DOI: 10.1021/acs.jmedchem.3c00750
Abstract

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.