title: Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics.
abstract: Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.
authors.affiliation: Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. rperni@sirtrispharma.com
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
authors.forename: Gurudatt
authors.initials: G
authors.lastname: Chandorkar
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cottrell
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Gates
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Kai
authors.initials: K
authors.lastname: Lin
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Luong
authors.forename: John P
authors.initials: JP
authors.lastname: Maxwell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Murcko
authors.forename: Janos
authors.initials: J
authors.lastname: Pitlik
authors.forename: Govinda
authors.initials: G
authors.lastname: Rao
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Schairer
authors.forename: John
authors.initials: J
authors.lastname: Van Drie
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006860:Hydrogen Bonding; D051379:Mice; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus