Sofosbuvir

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H373：Kann die Organe schädigen bei längerer oder wiederholter Exposition.

• Sicherheit

  P260：Dampf/Aerosol/Nebel nicht einatmen.

  P314：Bei Unwohlsein ärztlichen Rat einholen / ärztliche Hilfe hinzuziehen.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Sofosbuvir Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Sofosbuvir is a drug used for the treatment of hepatitis C. It is recommended to be used in combination with other drugs (such as velpatasvir) for the first-line treatment for HCV genotypes 1, 2, 3, 4, 5, and 6. It takes effect through acting as a nucleotide analog inhibitor, being capable of specially inhibiting the HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase.

• Originator

  Pharmasset (United States)

• Verwenden

  PSI-7977 is a prodrug that is metabolized to the active antiviral agent 2''-deoxy-2''-α-fluoro-β-C-methyluridine-5''-monophosphate and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. Studies have profiled PSI-7977 as a nucleotide inhibitor of hepatitis C virus, exerting selective inhibitory effects towards HCV NS5B polymerase.

• Verwenden

  PSI-7977 is a phosphoramidate prodrug of PSI-7851, a nucleoside analog that, when phosphorylated, inhibits the RNA-dependent RNA polymerase of hepatitis C virus (EC50 = 92 nM). PSI-7977 is effective in vitro and in vivo.[Cayman Chemical]

• Verwenden

  PSI-7977 is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-monophosphate and is currently being investigated in phase 3 clinical trials for the t reatment of hepatitis C. Studies have profiled PSI-7977 as a nucleotide inhibitor of hepatitis C virus, exerting selective inhibitory effects towards HCV NS5B polymerase.

• Definition

  ChEBI: A nucleotide conjugate that is used in combination with ledipasvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection.

• Trademarks

  Sovaldi

• Clinical Use

  In December 2013, sofosbuvir (also known as GS-7977 and PSI-7977) was approved in the United States for the treatment of hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen. Sofosbuvir was discovered from an effort to enhance the activity of the parent nucleoside by bypassing rate-limiting monophosphorylation with a prodrug that would liberate the intactmonophosphate in the liver, where it would then be converted by cellular kinases to the active triphosphate species. In addition, the prodrug was designed to be amenable to oral delivery. In the initial synthesis of sofosbuvir, the iso-propyl ester of (L)-alanine was coupled with phenyl dichlorophosphate to provide a diastereomeric intermediate that was coupled with the uridine nucleoside. The diastereomeric mixture (GS-9851) was shown to produce high levels of triphosphate in vitro in primary hepatocytes and in the livers of rats, dogs, and monkeys after oral dosing. The individual diastereomers were obtained by chromatography or by crystallization. The diastereomer with the Sp configuration at the phosphorous center (sofosbuvir) was found to be >10-fold more potent in an HCV replicon assay than the corresponding Rp diastereomer (EC_90s of 0.42 and 7.5 μM, respectively).

• Synthese

  The enantiopure unsaturated ester 166, which readily arises from olefination of the commercially-available aldehyde 165, was subjected to ethylene glycol-promoted permanganate dihydroxylation conditions to afford diol 167 in 60% yield over the two steps. A three-step sequence was then employed to generate lactone 169. Diol 167 was converted to the cyclic sulfite and then oxidized with bleach to give the corresponding cyclic sulfate. Treatment with nucleophilic fluorine gave intermediate ammonium sulfonate 168, which, upon acidic hydrolysis of both the acetonide and sulfonate, underwent cyclization to give lactone 169. Next, bis-protection of diol 169 furnished 170 in 71% yield for the four-step sequence. Reduction and chlorination through the use of Red-Al ® and sulfuryl chloride, respectively, constructed chlorotetrahydrofuran 171, which was subsequently reacted with commercial N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide 172 in the presence of base and Lewis acid to afford 173 in 57% yield over the two steps. Treatment of 173 with AcOH and then ammonia in MeOH removed all benzoyl protection to give rise to diol 174 in 78% yield. Finally, treatment of 174 with pentafluorophenolic phosphonate ester 175 and tert-butylmagnesium chloride generated sofosbuvir (XXII) in 68% yield. The final step proceeds with excellent chirality transfer from 175 (99.7% ee). Notably, the preparation of the key phosphonate fragment was achieved in a simple two-step sequence beginning with alanine isopropyl ester 176. Phosphorylation in the presence of base at cryogenic temperatures, followed by treatment with pentafluorophenol, delivered scale quantities of 176 in 34% isolated yield and high enantiopurity (>98% ee) after recrystallization.

• target

  HCV RNA-dependent RNA polymerase

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anti-arrhythmics: possibly increased risk of bradycardia with amiodarone.

• Stoffwechsel

  Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed in hepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS-331007, is inactive. It is formed through sequential and parallel pathways to the formation of active metabolite. The metabolic pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide binding protein followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
  Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was >92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. This data indicate that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted.

Sofosbuvir Upstream-Materialien And Downstream Produkte

Sofosbuvir Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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