Velpatasvir (formerly known as GS5816; GS-5816; VEL; trade name Vosevi) is a potent, selective, second-generation Hepatitis C virus NS5A protease inhibitor approved for clinical use with sofosbuvir in the treatment of hepatitis C infection of all six major genotypes. It inhibits hepatitis C viral replication through acting on the crucial 'membranous web' that facilitates RNA replication.
Physicochemical Properties
| Molecular Formula | C49H54N8O8 | |
| Molecular Weight | 883.00 | |
| Exact Mass | 882.406 | |
| Elemental Analysis | C, 66.65; H, 6.16; N, 12.69; O, 14.49 | |
| CAS # | 1377049-84-7 | |
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| PubChem CID | 67683363 | |
| Appearance | White to light yellow solid powder. | |
| Density | 1.3±0.1 g/cm3 | |
| Index of Refraction | 1.643 | |
| LogP | 6.78 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 10 | |
| Rotatable Bond Count | 13 | |
| Heavy Atom Count | 65 | |
| Complexity | 1690 | |
| Defined Atom Stereocenter Count | 6 | |
| SMILES | O(C([H])([H])[H])C([H])([H])[C@]1([H])C([H])([H])N(C([C@@]([H])(C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C(=O)OC([H])([H])[H])=O)[C@]([H])(C2=NC([H])=C(C3C([H])=C([H])C4=C(C([H])([H])OC5=C4C([H])=C4C([H])=C([H])C6=C(C4=C5[H])N=C([C@]4([H])C([H])([H])C([H])([H])[C@]([H])(C([H])([H])[H])N4C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(=O)OC([H])([H])[H])=O)N6[H])C=3[H])N2[H])C1([H])[H] |
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| InChi Key | FHCUMDQMBHQXKK-CDIODLITSA-N | |
| InChi Code | InChI=1S/C49H54N8O8/c1-26(2)41(54-48(60)63-5)47(59)57-27(3)12-17-38(57)45-51-36-16-14-30-20-35-33-15-13-31(19-32(33)25-65-40(35)21-34(30)43(36)53-45)37-22-50-44(52-37)39-18-28(24-62-4)23-56(39)46(58)42(55-49(61)64-6)29-10-8-7-9-11-29/h7-11,13-16,19-22,26-28,38-39,41-42H,12,17-18,23-25H2,1-6H3,(H,50,52)(H,51,53)(H,54,60)(H,55,61)/t27-,28-,38-,39-,41-,42+/m0/s1 | |
| Chemical Name | methyl ((R)-2-((2S,4S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate | |
| Synonyms | GS5816; GS-5816; GS 5816; Velpatasvir | |
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Velpatasvir (also known as GS-5816) is a novel pan-genotypic inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) with activity against genotype 1 (GT1) to GT6 HCV replicons. It is a selective inhibitor of HCV RNA replication with mean 50% effective concentrations (EC50s) against GT1 to GT6 of 6 to 130 pM. | ||
| ln Vivo |
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| Enzyme Assay | Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. | ||
| Cell Assay | Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of ≥3.3 log10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Oral bioavailability of 25-30%. 94% excreted in feces with 77% as parent compound. 0.4% excreted in urine. 1.4-1.6 L/kg. Estimated 0.12 L/h/kg [A19175. Metabolism / Metabolites Some metabolism by CYP2B6, CYP2C8, and CYP3A4. Biological Half-Life 15h. |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Velpatasvir has not been studied in nursing mothers being treated for hepatitis C infection. Because it is greater than 99% bound to maternal plasma proteins, amounts in breastmilk are likely to be very low. Some sources recommend against breastfeeding when velpatasvir is used with ribavirin. Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C. Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding >99.5% bound to plasma proteins. |
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| References |
[1]. Drug Des Devel Ther.2017 Feb 23;11:497-502. [2]. Antimicrob Agents Chemother.2016 Aug 22;60(9):5368-78. [3]. Signal Transduct Target Ther. 2021 May 29;6(1):212. |
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| Additional Infomation |
Pharmacodynamics Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A). At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 100~146.66 mg/mL ( 113.25~166.09 mM ) Water : ~100 mg/mL Ethanol : ~100 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (2.83 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (2.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.83 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1325 mL | 5.6625 mL | 11.3250 mL | |
| 5 mM | 0.2265 mL | 1.1325 mL | 2.2650 mL | |
| 10 mM | 0.1133 mL | 0.5663 mL | 1.1325 mL |