obeldesivir

{{Short description|Oral COVID-19 drug}}

{{Chembox

| ImageFile = Obeldesivir.svg

| ImageSize =

| IUPACName = [(2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methyl 2-methylpropanoate

| OtherNames =

| Section1 = {{Chembox Identifiers

| CASNo = 2647441-36-7

| CASNo_Ref = {{Cascite|changed|CAS}}

| ChEBI =

| ChEMBL = 4863829

| ChemSpiderID = 115037299

| DrugBank =

| EC_number =

| KEGG = D12776

| MeSHName =

| PubChem = 162513664

| UNII = Q55KCM7PXB

| InChI = 1S/C16H19N5O5/c1-8(2)15(24)25-5-10-12(22)13(23)16(6-17,26-10)11-4-3-9-14(18)19-7-20-21(9)11/h3-4,7-8,10,12-13,22-23H,5H2,1-2H3,(H2,18,19,20)/t10-,12-,13-,16+/m1/s1

| InChIKey = YIHPGVCWGSURHO-VSBTWAGUSA-N

| SMILES = CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@](O1)(C#N)C2=CC=C3N2N=CN=C3N)O)O

}}

| Section2 = {{Chembox Properties

| C=16 | H=19 | N=5 | O=5

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

}}

| Section3 = {{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

}}

Obeldesivir (GS-5245, ATV006) is an isobutyric ester prodrug of GS-441524 made by Gilead Sciences that is currently in Phase III trials for the outpatient treatment of COVID-19 in high risk patients.{{cite web | url=https://www.clinicaltrialsregister.eu/ctr-search/search?query=GS-5245 | title=Clinical Trials Register }}{{cite web | url=https://www.fiercepharma.com/pharma/gilead-touts-veklury-resilience-against-mutated-coronavirus-plots-phase-3-new-covid-oral | title=Gilead touts Veklury resilience against mutated coronavirus, plots phase 3 for new COVID oral antiviral | date=19 October 2022 }} The purpose of the isobutyric ester modification on obeldesivir is to improve the oral bioavailability of the parent nucleoside, GS-441524. Obeldesivir is hydrolyzed to its parent nucleoside, GS-441524, which is in turn converted to remdesivir-triphosphate (GS-443902) by a nucleoside kinase, adenylate kinase and nucleotide diphosphate kinase.{{cite journal | pmid=22446091 | year=2012 | last1=Cho | first1=A. | last2=Saunders | first2=O. L. | last3=Butler | first3=T. | last4=Zhang | first4=L. | last5=Xu | first5=J. | last6=Vela | first6=J. E. | last7=Feng | first7=J. Y. | last8=Ray | first8=A. S. | last9=Kim | first9=C. U. | title=Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides | journal=Bioorganic & Medicinal Chemistry Letters | volume=22 | issue=8 | pages=2705–2707 | doi=10.1016/j.bmcl.2012.02.105 | pmc=7126871 }}{{cite journal | doi=10.1021/acsmedchemlett.0c00316 | title=Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment | year=2020 | last1=Yan | first1=Victoria C. | last2=Muller | first2=Florian L. | journal=ACS Medicinal Chemistry Letters | volume=11 | issue=7 | pages=1361–1366 | pmid=32665809 | pmc=7315846 }}

GS-443902 is a bioactive ATP analogue with broad-spectrum antiviral activity {{cite journal | url=https://www.jbc.org/article/S0021-9258(17)48186-5/fulltext | pmid=32284326 | year=2020 | last1=Gordon | first1=C. J. | last2=Tchesnokov | first2=E. P. | last3=Woolner | first3=E. | last4=Perry | first4=J. K. | last5=Feng | first5=J. Y. | last6=Porter | first6=D. P. | last7=Götte | first7=M. | title=Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency | journal=The Journal of Biological Chemistry | volume=295 | issue=20 | pages=6785–6797 | doi=10.1074/jbc.RA120.013679 | pmc=7242698 | doi-access=free }} and is the same compound formed by remdesivir, though by a different enzymatic pathway. Unlike remdesivir, which is metabolized by enzymes that are highly expressed in the liver, GS-441524 released by obeldesivir is metabolized by enzymes that are evenly expressed throughout the body. Due to their different metabolic pathways, obeldesivir can be administered orally, whereas remdesivir must be administered intravenously for COVID-19 treatment.[https://file.medchemexpress.com/batch_PDF/HY-145994/Obeldesivir-DataSheet-MedChemExpress.pdf obeldesivir technical data sheet][https://www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi.pdf Remdesivir technical data sheet]

The pharmacokinetic properties of obeldesivir and improved was first published by Chinese researchers in May 2022. The Chinese group pursued investigation of obeldesivir independently from Gilead Sciences. Compared to IV administered GS-441524 in rats at 5 mg/kg, orally administered obeldesivir at 25 mg/kg (referred to as "ATV006") yielded approximately 22% bioavailability.{{cite journal | doi=10.1126/scitranslmed.abm7621 | title=The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants | year=2022 | last1=Cao | first1=Liu | last2=Li | first2=Yingjun | last3=Yang | first3=Sidi | last4=Li | first4=Guanguan | last5=Zhou | first5=Qifan | last6=Sun | first6=Jing | last7=Xu | first7=Tiefeng | last8=Yang | first8=Yang | last9=Liao | first9=Ruyan | last10=Shi | first10=Yongxia | last11=Yang | first11=Yujian | last12=Zhu | first12=Tiaozhen | last13=Huang | first13=Siyao | last14=Ji | first14=Yanxi | last15=Cong | first15=Feng | last16=Luo | first16=Yinzhu | last17=Zhu | first17=Yujun | last18=Luan | first18=Hemi | last19=Zhang | first19=Huan | last20=Chen | first20=Jingdiao | last21=Liu | first21=Xue | last22=Luo | first22=Renru | last23=Liu | first23=Lihong | last24=Wang | first24=Ping | last25=Yu | first25=Yang | last26=Xing | first26=Fan | last27=Ke | first27=Bixia | last28=Zheng | first28=Huanying | last29=Deng | first29=Xiaoling | last30=Zhang | first30=Wenyong | journal=Science Translational Medicine | volume=14 | issue=661 | pages=eabm7621 | pmid=35579533 | pmc=9161374 | display-authors=1 }} Treatment with obdeldesivir reduced viral load and prevents lung pathology in KI-hACE2 and Ad5-hACE2 mouse models of SARS-CoV-2. A patent filed by Gilead Sciences with a priority date of August 27, 2020,{{cite web | url=https://worldwide.espacenet.com/patent/search?q=pn%3DWO2022047065A2 | title=Espacenet – search results }} found the bioavailability of GS-441524 after oral administration of obdeldesivir (compound 15) in mice, rats, ferrets, dogs, and cynomolgus macaques to be 41%, 63.9%, 154%, 94%, and 38%, respectively. Across all species evaluated, obeldesivir showed improved oral bioavailability compared to oral administration of the parent nucleoside, GS-441524.{{cn|date=January 2023}}