Identification of Anthranilic Acid Derivatives as a Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase

2007 ◽  
Vol 50 (9) ◽  
pp. 2108-2116 ◽  
Author(s):  
Thomas Nittoli ◽  
Kevin Curran ◽  
Shabana Insaf ◽  
Martin DiGrandi ◽  
Mark Orlowski ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Anthranilic Acid ◽  
Allosteric Inhibitors ◽  
Ns5b Polymerase ◽  
Anthranilic Acid Derivatives

scholarly journals Identification of Anthranilic Acid Derivatives as a Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase.

2007 ◽  
Vol 50 (24) ◽  
pp. 6290-6290 ◽  
Author(s):  
Thomas Nittoli ◽  
Kevin Curran ◽  
Shabana Insaf ◽  
Martin DiGrandi ◽  
Mark Orlowski ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Anthranilic Acid ◽  
Allosteric Inhibitors ◽  
Ns5b Polymerase ◽  
Anthranilic Acid Derivatives

Potent Inhibitors of Subgenomic Hepatitis C Virus RNA Replication through Optimization of Indole-N-Acetamide Allosteric Inhibitors of the Viral NS5B Polymerase

2005 ◽  
Vol 48 (14) ◽  
pp. 4547-4557 ◽  
Author(s):  
Steven Harper ◽  
Salvatore Avolio ◽  
Barbara Pacini ◽  
Marcello Di Filippo ◽  
Sergio Altamura ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Replication ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Ns5b Polymerase

Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase — Acylsulfonamides and acylsulfamides as carboxylic acid replacements

2013 ◽  
Vol 91 (1) ◽  
pp. 66-81 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
René Coulombe ◽  
James Gillard ◽  
Christian Brochu ◽  
Jianmin Duan ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Carboxylic Acid ◽  
Allosteric Inhibitors ◽  
Subgenomic Replicon ◽  
Structure Activity ◽  
Hcv Ns5b ◽  
Acid Function ◽  
Ns5b Polymerase

Acylsulfonamide and acylsulfamide as surrogates for the carboxylic acid function of N-acetamide-indole-6-carboxylic acids were evaluated as allosteric inhibitors of hepatitis C virus (HCV) NS5B polymerase. Several analogs displayed excellent antiviral potency against both 1a and 1b HCV genotypes in cell-based subgenomic replicon assays. Structure–activity relationships (SAR) are discussed in the context of the crystal structure of an inhibitor − NS5B polymerase complex. Absorption, distribution, metabolism, and excretion pharmacokinetic (ADME-PK) properties of this class of inhibitors are also described.

Allosteric inhibitors of hepatitis C virus NS5B polymerase thumb domain site II: Structure-based design and synthesis of new templates

2010 ◽  
Vol 18 (8) ◽  
pp. 2836-2848 ◽  
Author(s):  
Savina Malancona ◽  
Monica Donghi ◽  
Marco Ferrara ◽  
Josè I. Martin Hernando ◽  
Marco Pompei ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Allosteric Inhibitors ◽  
Design And Synthesis ◽  
Thumb Domain ◽  
Ns5b Polymerase

scholarly journals Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

2012 ◽  
Vol 87 (3) ◽  
pp. 1544-1553 ◽  
Author(s):  
Doug J. Bartels ◽  
James C. Sullivan ◽  
Eileen Z. Zhang ◽  
Ann M. Tigges ◽  
Jennifer L. Dorrian ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Sustained Viral Response ◽  
Allosteric Inhibitors ◽  
Resistant Variant ◽  
Direct Acting Antiviral ◽  
Treatment Naïve ◽  
Variant Frequency ◽  
Direct Acting ◽  
Ns5b Polymerase

ABSTRACTThe prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC50]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC50) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

Non-Nucleoside Benzimidazole-Based Allosteric Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Inhibition of Subgenomic Hepatitis C Virus RNA Replicons in Huh-7 Cells

2004 ◽  
Vol 47 (27) ◽  
pp. 6884-6892 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
Yves Bousquet ◽  
Jean Gauthier ◽  
James Gillard ◽  
Martin Marquis ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Ns5b Polymerase

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

2016 ◽  
Vol 59 (13) ◽  
pp. 6293-6302 ◽  
Author(s):  
John J. Court ◽  
Carl Poisson ◽  
Andrzej Ardzinski ◽  
Darius Bilimoria ◽  
Laval Chan ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Allosteric Inhibitors ◽  
Ns5b Polymerase
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