title: TMC-435, an NS3/4A protease inhibitor for the treatment of HCV infection.
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.
authors: McGill University, Chemistry Department, 801 Sherbrooke Street West, Montréal, Quebec, Canada. youla.tsantrizos@mcgill.ca
authors: Youla S
authors: YS
authors: Tsantrizos
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D000069616:Simeprevir; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D006575:Heterocyclic Compounds, 3-Ring; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C417083:peginterferon alfa-2b