bemnifosbuvir   Click here for help

GtoPdb Ligand ID: 11295

Synonyms: AT-527 | AT527 | RO-7496998 | RO7496998
Compound class: Synthetic organic
Comment: AT-527 is the orally bioavailable hemi-sulfate salt of AT-511, which is a direct-acting antiviral compound that disrupts activity of the viral RNA polymerase [1]. It was originally developed to combat hepatitis C (HCV) infection, but has been redeployed for SARS-CoV-2. Chemically AT-527 is a phosphoramidate purine nucleotide and it is metabolised to a biologically active guanosine triphosphate analogue in vivo. Preclinical results showing pan-genotype activity against HCV were published in early 2020 [2]. In October 2020 anti-SARS-CoV-2 activity was reported in preprint format [3], which converted to full peer reviewed publication in March 2021 [4].

AT-527 was developed by Atea Pharmaceuticals [5]. In October 2020 it was announced that Roche were purchasing the rights to AT-527 (and gave it the research code RO7496998) outside of the US. In the same press release, it was revealed that AT-527 would be evaluated in Phase 3 trial in early 2021 to determine its efficacy as an early treatment for COVID-19 in non-hospitalised patients.

This is a complex molecule with 5 stereo-centres, so there are several CIDs with the same connectivity in PubChem. We chose to represent the molecule from CID 122527275 as it is linked to a FDA UNique Ingredient Identifier (UNII) code. This CID represents the parent molecule. For the hemi-sulfate salt structure see PubChem CID 155926085.
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 12
Hydrogen bond donors 4
Rotatable bonds 12
Topological polar surface area 194.78
Molecular weight 581.22
XLogP 2.31
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
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Canonical SMILES CNc1nc(N)nc2c1ncn2[C@@H]1O[C@@H]([C@H]([C@@]1(C)F)O)CO[P@@](=O)(N[C@H](C(=O)OC(C)C)C)Oc1ccccc1
Isomeric SMILES C[C@@H](C(=O)OC(C)C)N[P@](=O)(OC[C@@H]1[C@H]([C@@]([C@@H](O1)n1cnc2c(nc(nc12)N)NC)(C)F)O)Oc1ccccc1
InChI InChI=1S/C24H33FN7O7P/c1-13(2)37-21(34)14(3)31-40(35,39-15-9-7-6-8-10-15)36-11-16-18(33)24(4,25)22(38-16)32-12-28-17-19(27-5)29-23(26)30-20(17)32/h6-10,12-14,16,18,22,33H,11H2,1-5H3,(H,31,35)(H3,26,27,29,30)/t14-,16+,18+,22+,24+,40-/m0/s1
InChI Key OISLSHLAXHALQZ-LZEIJKKFSA-N
References
1. Berliba E, Bogus M, Vanhoutte F, Berghmans PJ, Good SS, Moussa A, Pietropaolo K, Murphy RL, Zhou XJ, Sommadossi JP. (2019)
Safety, pharmacokinetics and antiviral activity of AT-527, a novel purine nucleotide prodrug, in HCV-infected subjects with and without cirrhosis.
Antimicrob Agents Chemother, [Epub ahead of print]. [PMID:31570394]
2. Good SS, Moussa A, Zhou XJ, Pietropaolo K, Sommadossi JP. (2020)
Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus.
PLoS One, 15 (1): e0227104. [PMID:31914458]
3. Good SS, Westover J, Jung KH, La Colla P, Collu G, Moussa A, Canard B, Sommadossi J-P. (2020)
AT-527 is a potent in vitro replication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic.
bioRxiv, Preprint. DOI: 10.1101/2020.08.11.242834
4. Good SS, Westover J, Jung KH, Zhou XJ, Moussa A, La Colla P, Collu G, Canard B, Sommadossi JP. (2021)
AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.
Antimicrob Agents Chemother, 65 (4). DOI: 10.1128/AAC.02479-20 [PMID:33558299]
5. Moussa A, Sommadossi J-P. (2018)
Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus.
Patent number: WO2018144640A1. Assignee: Atea Pharmaceuticals, Inc.. Priority date: 01/02/2017. Publication date: 09/08/2018.