Synthesis and SAR studies of novel heteroaryl fused tetracyclic indole-diamide compounds: Potent allosteric inhibitors of the hepatitis C virus 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.

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Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

Journal of Computer-Aided Molecular Design ◽

10.1007/s10822-008-9230-7 ◽

2008 ◽

Vol 22 (10) ◽

pp. 711-725 ◽

Cited By ~ 9

Author(s):

Beilei Lei ◽

Juan Du ◽

Shuyan Li ◽

Huanxiang Liu ◽

Yueying Ren ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Molecular Similarity ◽

Field Analysis ◽

Molecular Field ◽

Comparative Molecular Field Analysis ◽

Allosteric Inhibitors ◽

Molecular Field Analysis ◽

Similarity Indices ◽

Ns5b Polymerase

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

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2010.03.024 ◽

2010 ◽

Vol 18 (8) ◽

pp. 2836-2848 ◽

Cited By ~ 17

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

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

Journal of Virology ◽

10.1128/jvi.02294-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1544-1553 ◽

Cited By ~ 115

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.

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