Abstract
TMC-435, being developed by Tibotec Pharmaceuticals Ltd, is an orally administered, macrocyclic inhibitor of the HCV NS3/4A serine protease. HCV infection can cause chronic hepatitis, cirrhosis of the liver and hepatocellular carcinoma. The HCV NS3/4A enzyme is an essential component for viral replication, suggesting that this protein is a key therapeutic target. Biochemical assays demonstrated potent inhibition of HCV NS3/4A by TMC-435 in all HCV genotypes tested, with the exception of HCV-3. In cellular replicon models, the compound selectively inhibited HCV-1 replication and displayed additive effects with ribavirin, and had synergistic activity with IFNalpha and an NS5B polymerase inhibitor. Pharmacokinetic data demonstrated high exposure and good oral bioavailability, supporting once-daily dosing of TMC-435 in humans. In phase I and II clinical trials, the administration of TCM-435 to patients infected with HCV-1, alone or in combination with PEG-IFNalpha and ribavirin, produced significant reductions in HCV-RNA without any significant adverse effects, thus providing a basis for further development of this compound as an anti-HCV therapeutic agent. At the time of publication, phase II trials with TMC-435 were ongoing.
MeSH terms
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Animals
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Antiviral Agents / therapeutic use
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Clinical Trials as Topic
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Drug Synergism
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Drug Therapy, Combination
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Hepacivirus / drug effects
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Hepacivirus / enzymology
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Hepatitis C, Chronic / drug therapy*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Heterocyclic Compounds, 3-Ring / therapeutic use*
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Humans
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Interferon alpha-2
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Interferon-alpha / therapeutic use
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Intracellular Signaling Peptides and Proteins
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Polyethylene Glycols / therapeutic use
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Protease Inhibitors / therapeutic use*
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Recombinant Proteins
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Ribavirin / therapeutic use
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Simeprevir
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / metabolism
Substances
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Antiviral Agents
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Carrier Proteins
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Heterocyclic Compounds, 3-Ring
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Interferon alpha-2
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Interferon-alpha
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Intracellular Signaling Peptides and Proteins
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NS3 protein, hepatitis C virus
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NS4A cofactor peptide, Hepatitis C virus
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Protease Inhibitors
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Recombinant Proteins
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Sulfonamides
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Viral Nonstructural Proteins
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Viral Proteins
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Polyethylene Glycols
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Ribavirin
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Simeprevir
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peginterferon alfa-2b