Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys
Journal of Medicinal Chemistry(2023)
摘要
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 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 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 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.
### Competing Interest Statement
Some authors may be stockholders of Gilead Sciences.
* AB
: apical to basolateral
AGM
: African green monkey
ATP
: adenosine triphosphate
BALF
: bronchioalveolar lavage fluid
BEGM
: bronchial epithelial growth medium
CES
: carboxyesterase
Cyno
: cynomolgus
DIC
: N , N ′-Diisopropylcarbodiimide
DMAP
: 4-dimethylaminopyridine
DMEM
: Dulbecco’s modified eagle medium dpi, day post-infection
FBS
: fetal bovine serum
GI
: gasterointestinal
gRNA
: genomic RNA
Hep
: Hepatocytes hr, human recombinant
IACUC
: International animal care and use committee
IV
: intravenous
LLOQ
: lower limit of quantification
MERS
: Middle East Respiratory Syndrome
MOI
: multiplicity of infection
NHBE
: normal human bronchial epithelial
NHP
: non-human primate
NTP
: nucleotide triphosphate
PBMC
: peripheral blood mononuclear cells
PBS
: phosphate-buffered saline
PFA
: Plaque forming assay
PFU
: plaque forming unit
PHH
: primary human hepatocyte
PMSF
: phenylmethylsulfonyl fluoride
RdRp
: RNA-dependent RNA polymerase
RSV
: respiratory syncytial virus
SARS
: severe acute respiratory syndrome
VOC
: variant of concern
WHO
: World Health Organization
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