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361.35 g/mol


[(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



Obeldesivir (GS-5245ATV006) 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.[1][2] 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.[3][4]

GS-443902 is a bioactive ATP analogue with broad-spectrum antiviral activity [5] 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.[citation needed]

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.[6] 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,[7] 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




Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP2-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.

Synthesis of ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl Isobutyrate (3)

To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 4 (2000 mg, 6.0 mmol) (30) and isobutyric acid (638 mg, 7.2 mmol) in DMF (5 mL), N,N′-diisopropylcarbodiimide (914 mg, 7.2 mmol) was slowly added followed by 4-(dimethylamino)pyridine (737 mg, 6.0 mmol). The reaction mixture was stirred for 4 h and then diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20% MeOH in CH2Cl2 to provide the intermediate ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate. LCMS m/z = 402.2 (M + 1). To a solution of the intermediate (1500 mg) in THF (10 mL), conc. HCl (2 mL) was added, and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with CH2Cl2, washed with water, saturated aqueous bicarbonate, and brine, dried over sodium sulfate, concentrated, and subjected to silica gel chromatography, eluting with 30% MeOH in CH2Cl2 to afford the title compound (660 mg, 50%). 1H NMR (400 MHz, MeOH-d4) δ 7.88 (s, 1H), 6.96–6.85 (m, 2H), 4.50–4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H). LCMS m/z: 362.1 (M + 1). 13C NMR (400 MHz, CHCl3d3) δ 175.9, 155.6, 147.9, 123.5, 110.2, 100.8, 116.9, 116.6, 81.3, 79.0, 74.0, 70.2, 62.9, 33.2, 18.7, 18.6. HRMS m/z: 362.14615, C16H20N5O5 362.14644.






Example 1. (3aR, 4R, 6R, 6aR)-4-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl- Synthesis of 2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolyl-4-carbonitrile (compound 5)


        Dissolve 5.62g of compound 69-0 in 30mL of acetone, then add 11.50mL of 2,2-dimethoxypropane and 1.34mL of 98% sulfuric acid, stir at 45°C for half an hour, cool to room temperature, and remove by rotary evaporation Organic solvents. Extract with 100 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution. Repeat the extraction three times. Combine the ethyl acetate layers, add anhydrous sodium sulfate to dry, and filter to remove sodium sulfate. The organic solvent was removed by rotary evaporation, and 6.20 g of compound 5 (white solid, yield 97%) was obtained through column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2). The hydrogen spectrum of the obtained compound 5 was detected, and the results are as follows:
        氢谱:1H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.11(d,J=4.7Hz,1H),6.69(dd,J=4.8,2.4Hz,1H),5.77(s,2H),5.42(d,J=6.6Hz,1H),5.24(dd,J=6.6,2.4Hz,1H),4.67(q,J=1.9Hz,1H),3.99(dd,J=12.5,1.9Hz,1H),3.84(dd,J=12.5,1.7Hz,1H),1.81(s,3H),1.40(s,3H)。
        Example 2. ((3aR,4R,6R,6aR)-6-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2 ,Synthesis of 2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methylisobutyrate (compound INT-1)

        Dissolve 1.50g of compound 5 in 15ml of dichloromethane, then add 0.42mL of isobutyric acid and 55.40mg of 4-dimethylaminopyridine, stir for 10 minutes, add 1.02g of dicyclohexylcarbodiimide, and stir at room temperature. Stir for 24h. After column chromatography separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/1), 1.71 g of compound INT-1 (white solid, yield 94%) was obtained. The hydrogen spectrum and carbon spectrum of the obtained compound INT-1 were detected, and the results are as follows:
        Hydrogen spectrum: 1 H NMR (400MHz, CDCl 3 ,ZQF-RD01-2)δ(ppm):7.99(s,1H),6.99(d,J=4.6Hz,1H),6.62(d,J=4.6Hz,1H),5.72(br,2H),5.49(d,J=6.8Hz,1H),4.93-4.90(dd,J=6.8Hz,4.3Hz,1H),4.61-4.58(q,J=4.4Hz,1H),4.44-4.26(m,2H),2.61-2.50(m,1H),1.77(s,3H),1.42(s,3H),1.17-1.14(q,J=3.8Hz,6H)。
        Carbon spectrum: 13 C NMR (100MHz, CDCl 3 ,ZQF-RD01-2)δ(ppm):176.7,155.2,147.3,123.5,117.2,116.7,115.6,112.6,100.0,83.8,83.0,82.0,81.4,63.1,33.8,26.4,25.6,18.9。




To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, Intermediate 1 (2000 mg, 6.0 mmol) (Siegel et. al. J. Med. Chem.2017, 60, 1648-1661) in tetrahydrofuran (THF) was added N,N-dimethylaminopyridine (DMAP) (0.03 eq). To the reaction mixture, isobutyric anhydride (1.1 eq) was added slowly. After the completion of the staring material, the reaction mixture was concentrated and purified by flash chromatography using 20% methanol in DCM as an eluant to give ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate, Intermediate 1a. LCMS: MS m/z: 402.2 (M+1).

Concentrated HCl (5 eq, 1mL) was added to a solution of Intermediate 1a (1000 mg) in acetonitrile (10 mL), which was then stirred at room temperature for 2 hours. LCMS showed the product formation. The reaction was stopped after 4 hours. The reaction mixture was diluted with ethyl acetate and quenched with saturated bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulphate, and concentrated. The residue was purified by flash chromatography using 30% methanol DCM as an eluant. The collected fractions were concentrated to give Intermediate 2.1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 6.96 – 6.85 (m, 2H), 4.50 – 4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H); LCMS: MS m/z: 362.1 (M+1).

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IUPAC name

[(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
3D model (JSmol)
PubChem CID

Molar mass 361.358 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).


  1. ^ “Clinical Trials Register”.
  2. ^ “Gilead touts Veklury resilience against mutated coronavirus, plots phase 3 for new COVID oral antiviral”. 19 October 2022.
  3. ^ Cho, A.; Saunders, O. L.; Butler, T.; Zhang, L.; Xu, J.; Vela, J. E.; Feng, J. Y.; Ray, A. S.; Kim, C. U. (2012). “Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides”Bioorganic & Medicinal Chemistry Letters22 (8): 2705–2707. doi:10.1016/j.bmcl.2012.02.105PMC 7126871PMID 22446091.
  4. ^ Yan, Victoria C.; Muller, Florian L. (2020). “Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment”ACS Medicinal Chemistry Letters11 (7): 1361–1366. doi:10.1021/acsmedchemlett.0c00316PMC 7315846PMID 32665809.
  5. ^ Gordon, C. J.; Tchesnokov, E. P.; Woolner, E.; Perry, J. K.; Feng, J. Y.; Porter, D. P.; Götte, M. (2020). “Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency”The Journal of Biological Chemistry295 (20): 6785–6797. doi:10.1074/jbc.RA120.013679PMC 7242698PMID 32284326.
  6. ^ Cao, Liu; et al. (2022). “The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants”Science Translational Medicine14 (661): eabm7621. doi:10.1126/scitranslmed.abm7621PMC 9161374PMID 35579533.
  7. ^ “Espacenet – search results”.

//////////Obeldesivir, GS-5245ATV006


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