Novel, potent phenethylamide inhibitors of the hepatitis C virus (HCV) NS3 protease: probing the role of P2 aryloxyprolines with hybrid structures.
Synthesis of hybrid HCV NS3 protease/NS4A inhibitors having the 4,4-difluoroaminobutyric acid (difluoroAbu) phenethylamides as P1-P1' and quinolyloxyprolines as P2 fragments led to 7 (IC(50) 54 nM). Molecular modelling suggests that this potent tripeptide inhibitor utilizes interactions in the S1', S1, S2, S3 and S4 sites of the protease.
Orvieto
Federica
F
Medicinal Chemistry Department, IRBM-MRL Rome, V Pontina Km 30,600, 00040 Pomezia, Rome, Italy.
Koch
Uwe
U
Matassa
Victor G
VG
Muraglia
Ester
E
D000613:Aminobutyrates / Q000737:chemistry; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006873:Hydroquinones / Q000737:chemistry; D006909:Hydroxyproline / Q000737:chemistry; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020365:RNA Helicases; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000613:Aminobutyrates; D000814:Aniline Compounds; D000998:Antiviral Agents; D006873:Hydroquinones; D006909:Hydroxyproline; D009842:Oligopeptides; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases