Discovery of SCH446211 (SCH6): a new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication.
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.
Bogen
Stéphane L
SL
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Stephane.Bogen@spcorp.com
Arasappan
Ashok
A
Bennett
Frank
F
Chen
Kevin
K
Jao
Edwin
E
Liu
Yi-Tsung
YT
Lovey
Raymond G
RG
Venkatraman
Srikanth
S
Pan
Weidong
W
Parekh
Tajel
T
Pike
Russel E
RE
Ruan
Sumei
S
Liu
Rong
R
Baroudy
Bahige
B
Agrawal
Sony
S
Chase
Robert
R
Ingravallo
Paul
P
Pichardo
John
J
Prongay
Andrew
A
Brisson
Jean-Marc
JM
Hsieh
Tony Y
TY
Cheng
Kuo-Chi
KC
Kemp
Scott J
SJ
Levy
Odile E
OE
Lim-Wilby
Marguerita
M
Tamura
Susan Y
SY
Saksena
Anil K
AK
Girijavallabhan
Viyyoor
V
Njoroge
F George
FG
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
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