1535212-07-7

Basic information

• Product Name: GS9857
• Synonyms: GS9857;Voxilaprevir
• CAS NO: 1535212-07-7
• Molecular Formula: C₄₀H₅₂F₄N₆O₉S
• Molecular Weight: 868.9342928
• EINECS: -0
• Mol File: 1535212-07-7.mol
• Article Data: 2

Chemical Properties

• Appearance: /
• Density: 1.42±0.1 g/cm3(Predicted)
• PKA: 4.46±0.40(Predicted)
• CAS DataBase Reference: GS9857(CAS DataBase Reference)
• NIST Chemistry Reference: GS9857(1535212-07-7)
• EPA Substance Registry System: GS9857(1535212-07-7)

Safety Data

• Hazardous Substances Data: 1535212-07-7(Hazardous Substances Data)

Usage

Description

GS9857, also known as Voxilaprevir, is a Direct-Acting Antiviral (DAA) medication developed by Gilead. It is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that works by reversibly binding and inhibiting the NS3/4A serine protease of HCV. This action prevents viral replication and function, making it an essential component in the treatment of chronic Hepatitis C.

Uses

Used in Pharmaceutical Industry:
GS9857 is used as a hepatitis C treatment for patients with chronic HCV infection. It is part of a fixed-dose combination therapy with sofosbuvir and velpatasvir, which has the trade name Vosevi. This combination therapy is effective against various HCV genotypes, including genotypes 1, 2, 3, 4, 5, and 6.
Used in Hepatitis C Treatment:
GS9857 is used as a Direct-Acting Antiviral (DAA) medication for the treatment of chronic Hepatitis C, an infectious liver disease caused by the Hepatitis C Virus (HCV). It is particularly effective in patients who have been previously treated with an NS5A inhibitor or patients with genotypes 1a or 3 infection who have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.
Used in Combination Therapy:
GS9857 is used in combination with sofosbuvir and velpatasvir to form the commercially available product Vosevi. This fixed-dose combination therapy has been approved for the treatment of adult patients with chronic HCV infection, offering a new treatment option for those who have failed previous regimens containing an NS5A inhibitor.
Appearance:
GS9857 is an off-white solid.

Mechanism of Action

Voxilaprevir is an orally bioavailable inhibitor of the hepatitis C virus (HCV) non-structural protein 3/non-structural protein 4A (NS3/NS4A) serine protease, with antiviral activity. Upon administration, voxilaprevir binds to the HCV NS3/NS4A serine protease and prevents NS3/NS4A protease-mediated polyprotein maturation. This disrupts both the processing of viral proteins and the formation of the viral replication complex, thereby preventing viral replication and function. NS3, a serine protease, is essential for the proteolytic cleavage of multiple sites within the HCV polyprotein and plays a key role during HCV ribonucleic acid (RNA) replication. NS4A is an activating factor for NS3. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).

Synthetic route

methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate (1026200-25-8) → (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1 R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,1 0,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (1535212-07-7)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: lithium hydroxide monohydrate / water; methanol / 4 h / 60 °C 2.1: sodium periodate; osmium(VIII) oxide / water; tetrahydrofuran / 72 h 3.1: sodium tetrahydroborate / methanol / 6 h / 0 - 20 °C 4.1: ortho-nitrophenyl selenocyanate; tributylphosphine / tetrahydrofuran / 0.42 h / 0 - 20 °C 4.2: 2 h / 0 - 60 °C 5.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C 6.1: 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(iso-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methylene ruthenium(II) dichloride / 1,2-dichloro-ethane / 1.33 h / 100 °C / Inert atmosphere 7.1: palladium 10% on activated carbon; hydrogen / ethanol / 2.5 h / 760.05 Torr 8.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 9.1: N-ethyl-N,N-diisopropylamine; HATU; dmap / N,N-dimethyl-formamide / 0.67 h / 20 °C View Scheme

Upstream product

• 1026200-25-8 methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate 
• 1026200-27-0 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine 
• 1535210-59-3 C₁₄H₂₃NO₅ 
• 1535210-60-6 C₁₄H₂₅NO₅ 
• 1535210-61-7 C₁₄H₂₃NO₄ 
• 1294512-26-7 ethyl 3,3-difluoro-2-oxopent-4-enoate 
• 1535210-94-6 C₁₂H₉ClF₂N₂O 
• 1535212-03-3 C₃₇H₅₀F₂N₄O₇ 
• 1535212-05-5 C₃₅H₄₈F₂N₄O₇ 
• 1535212-06-6 C₃₁H₄₀F₂N₄O₇ 
• 1360828-80-3 C₉H₁₄F₂N₂O₃S*ClH 

Relevant articles and documents

Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.