title: Discovery of SCH446211 (SCH6): a new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication.
abstract: Introduction of various modified prolines at P(2) and optimization of the P(1) side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K(i)*= 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC(50) and IC(90) of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Stephane.Bogen@spcorp.com
authors.forename: Stéphane L
authors.initials: SL
authors.lastname: Bogen
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Edwin
authors.initials: E
authors.lastname: Jao
authors.forename: Yi-Tsung
authors.initials: YT
authors.lastname: Liu
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Lovey
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.forename: Tajel
authors.initials: T
authors.lastname: Parekh
authors.forename: Russel E
authors.initials: RE
authors.lastname: Pike
authors.forename: Sumei
authors.initials: S
authors.lastname: Ruan
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Bahige
authors.initials: B
authors.lastname: Baroudy
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.forename: Paul
authors.initials: P
authors.lastname: Ingravallo
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Brisson
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Hsieh
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Kemp
authors.forename: Odile E
authors.initials: OE
authors.lastname: Levy
authors.forename: Marguerita
authors.initials: M
authors.lastname: Lim-Wilby
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Tamura
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saksena
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016679:Genome, Viral / Q000235:genetics*; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D051381:Rats; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000577:Amides; D009842:Oligopeptides; D012367:RNA, Viral; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C510133:SCH6