TMC647055, a Potent Nonnucleoside Hepatitis C Virus NS5B Polymerase Inhibitor with Cross-Genotypic Coverage

Devogelaere, Benoit; Berke, Jan Martin; Vijgen, Leen; Dehertogh, Pascale; Fransen, Els; Cleiren, Erna; Helm, Liesbet van der; Nyanguile, Origène; Tahri, Abdellah; Amssoms, Katie; Lenz, Oliver; Cummings, Maxwell D.; Clayton, R. M.; Vendeville, Sandrine; Raboisson, Pierre; Simmen, Kenneth; Fanning, Gregory; Lin, Tse I.

doi:10.1128/aac.00245-12

Cited by 40 publications

(28 citation statements)

References 46 publications

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“…Emerging TMC647055 RAVs were found at time of failure in the majority of patients (in 14/17 and 2/5 patients with virologic failure in the 2- and 3-DAA regimens, respectively). These were observed at NS5B position 495 only, similar to the findings from in vitro TMC647055 selection experiments [11] and from the Phase 1b study that evaluated TMC647055 in monotherapy and in combination with SMV [12, 13]. There was no difference found in emerging RAVs between a low dose of TMC647055/RTV (450 mg QD; Panels 1–2) and a high dose (600 mg QD; Panel 3) or between HCV geno/subtypes.…”

Section: Discussionsupporting

confidence: 85%

Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Vijgen

Thys

Vandebosch

et al. 2017

Virol J

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BackgroundIn study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001.MethodsHCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates.ResultsThe majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients.ConclusionsVirologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study.Trial registration number NCT01724086 (date of registration: September 26, 2012)Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0760-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Vijgen

Thys

Vandebosch

et al. 2017

Virol J

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“…TMC647055 25 (Fig. 3), a nonzwitterionic 17-membered macrocyclic indole, has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase [51]. Lead optimization from 20 to 25 in conjunction with in vivo evaluation in rats identified this compound showing nanomolar potency (EC 50 ¼ 77 nM) in HCV replicon cells, limited toxicity and offetarget activities, and encouraging preclinical pharmacokinetic profiles characterized by high liver distribution, and it is currently being evaluated in phase II clinical trials in combination with simeprevir [52].…”

Section: Indole Antiviral Agents: Drugs On Market or Compounds In CLImentioning

confidence: 99%

A review on recent developments of indole-containing antiviral agents

Zhang

Chen

Yang

2015

European Journal of Medicinal Chemistry

679

208

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Indole represents one of the most important privileged scaffolds in drug discovery. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes, which provide tremendous opportunities to discover novel drugs with different modes of action. There are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. There are also an amazing number of approved indole-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. This review focused on the recent development of indole derivatives as antiviral agents with the following objectives: 1) To present one of the most comprehensive listings of indole antiviral agents, drugs on market or compounds in clinical trials; 2) To focus on recent developments of indole compounds (including natural products) and their antiviral activities, summarize the structure property, hoping to inspire new and even more creative approaches; 3) To offer perspectives on how indole scaffolds as a privileged structure might be exploited in the future.

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“…The next review in this series contains some extraordinary molecules as described by Siddappa, Shivaputra and Renukadevi Patil; (benz)imidazole‐and indole‐based macrocycles might seem terribly familiar but dicationic structures such as 12 are notably active against bacteria. [ ] Away from these exotic structures, the use of macrocycles in mainstream drug discovery is demonstrated by the clinical candidate TMC647055 13 , a potent inhibitor (77 n m ) of the NS5B polymerase from hepatitis C virus [ ] (Figure ).…”

Section: Comparison Of Lipinski Ro5 With Ppi Inhibitors and Macrocyclmentioning

confidence: 99%

Macrocycles, the edge of drug‐likeness chemical space or Goldilocks zone?

Selwood

2017

Chem Biol Drug Des

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TMC647055, a Potent Nonnucleoside Hepatitis C Virus NS5B Polymerase Inhibitor with Cross-Genotypic Coverage

Cited by 40 publications

References 46 publications

Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

A review on recent developments of indole-containing antiviral agents

Macrocycles, the edge of drug‐likeness chemical space or Goldilocks zone?

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