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

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

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.

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