Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics.
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.
Perni
Robert B
RB
Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. rperni@sirtrispharma.com
Chandorkar
Gurudatt
G
Cottrell
Kevin M
KM
Gates
Cynthia A
CA
Lin
Chao
C
Lin
Kai
K
Luong
Yu-Ping
YP
Maxwell
John P
JP
Murcko
Mark A
MA
Pitlik
Janos
J
Rao
Govinda
G
Schairer
Wayne C
WC
Van Drie
John
J
Wei
Yunyi
Y
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
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