Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.
We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
Arasappan
A
A
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. ashok.arasappan@spcorp.com
Njoroge
F G
FG
Chan
T-Y
TY
Bennett
F
F
Bogen
S L
SL
Chen
K
K
Gu
H
H
Hong
L
L
Jao
E
E
Liu
Y-T
YT
Lovey
R G
RG
Parekh
T
T
Pike
R E
RE
Pinto
P
P
Santhanam
B
B
Venkatraman
S
S
Vaccaro
H
H
Wang
H
H
Yang
X
X
Zhu
Z
Z
Mckittrick
B
B
Saksena
A K
AK
Girijavallabhan
V
V
Pichardo
J
J
Butkiewicz
N
N
Ingram
R
R
Malcolm
B
B
Prongay
A
A
Yao
N
N
Marten
B
B
Madison
V
V
Kemp
S
S
Levy
O
O
Lim-Wilby
M
M
Tamura
S
S
Ganguly
A K
AK
D001665:Binding Sites; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000737:chemistry*; D015394:Molecular Structure; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D015842:Serine Proteinase 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