title: In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.
abstract: The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC(50)) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC(99) value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.
authors.affiliation: Tibotec BVBA, Gen De Wittelaan L11 B3, Mechelen, Belgium. tilin@its.jnj.com
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.forename: Gregory
authors.initials: G
authors.lastname: Fanning
authors.forename: Thierry
authors.initials: T
authors.lastname: Verbinnen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Delouvroy
authors.forename: Annick
authors.initials: A
authors.lastname: Scholliers
authors.forename: Katrien
authors.initials: K
authors.lastname: Vermeiren
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Michael
authors.initials: M
authors.lastname: Edlund
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Herman
authors.initials: H
authors.lastname: de Kock
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069616:Simeprevir; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080107:NS4B protein, flavivirus