HCV NS5B Polymerase Inhibitors

Burton, J.; Everson, Gregory T.

doi:10.1016/j.cld.2009.05.001

Cited by 60 publications

(96 citation statements)

References 24 publications

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“…(E)-Hex-3-deutero-2-en-1-ol (5). To a three-neck 250 mL round-bottom flask equipped with mechanical stirrer and reflux condenser was charged 2-hexyn-1-ol 4 (10 g, 0.1 mol) and THF (100 mL, 10 vol).…”

Section: Methodsmentioning

confidence: 99%

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In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

et al. 2009

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Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCV(a)) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a approximately 13% increase of AUC for 1.

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Section: Methodsmentioning

confidence: 99%

“…Blood samples were collected from each rat at 0 (predose), 0.25, 0.5, 1, 1. 5,2,4,6,8,12, and 24 h after oral dosing. Blood samples (0.250 mL) were collected using the Instech Automated Blood Samples (Model ABS11, Instech Laboratories, Plymouth Meeting, PA) into EDTA containing tubes that were maintained at 4°C.…”

mentioning

confidence: 99%

In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

et al. 2009

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“…It has been shown to interact with an extensive array of host proteins and to play a role in IFN resistance (37,40). NS5B is the RNA-dependent RNA polymerase responsible for replication of HCV RNA (1,4).…”

mentioning

confidence: 99%

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Pelosi

Voss

Liu

et al. 2012

Antimicrob Agents Chemother

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Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additivesynergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic. H epatitis C virus (HCV) is a positive-stranded RNA virus in theFlaviviridae family of enveloped virions which affects an estimated 170 million people worldwide and is the major cause of chronic hepatitis. Currently, approximately 50% of patients infected with genotype 1 (gt 1), the most prevalent form of the virus, fail to achieve a sustained reduction in viral load with therapy employing pegylated alpha interferon (IFN-␣) plus ribavirin (alfa/RBV) (52,54,56). A substantial fraction (20%) of chronically infected patients develop serious progressive liver disease, including cirrhosis or hepatocellular carcinoma. alfa/RBV treatment is associated with a high incidence (Ͼ30%) of adverse effects, some of which are of sufficient severity to cause patients to discontinue therapy (56). Despite the recent approval of two new direct-acting antiviral agents (DAAs), boceprevir and telaprevir, for use in combination with alfa/RBV (18, 47), their use may be limited by poor efficacy in some patient populations, inconvenient 3-times-daily dosing of the DAA, and association with side effects, including anemia, rash, and gastrointestinal effects, in addition to the well-documented spectrum of adverse effects associated with alfa/RBV. Although addition of these DAAs to the standard of care for HCV represents a significant i...

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“…This prodrug approach did result in significantly improved pharmacokinetic properties, and clinical studies showed that mericitabine was efficacious in humans. Patients administered a twice-daily dose of 1500 mg produced a −2.7 log 10 (IU ⋅ mL −1 ) reduction in viral load after 14 days of monotherapy in GT 1 naïve patients, and in combination with PEG-IFN/RBV for 28 days in GT 1, 2 and 3 patients, mericitabine delivered rapid virological response (RVR) rates of 85-90% with no reported significant adverse events and no viral breakthroughs [21,26,27]. These results demonstrated for the first time that a DAA could be effective in patients infected with not only GT 1 but also GT 2 and 3 viruses and that a nucleoside was capable of demonstrating a high barrier to resistance in multiple genotypes.…”

Section: Target Rationale: Hcv Ns5b Rna-dependent Rna Polymerasementioning

confidence: 99%

Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus

Sofia¹

2016

Successful Drug Discovery

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HCV NS5B Polymerase Inhibitors

Cited by 60 publications

References 24 publications

In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus

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