5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
Ellis
David A
DA
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Blazel
Julie K
JK
Tran
Chinh V
CV
Ruebsam
Frank
F
Murphy
Douglas E
DE
Li
Lian-Sheng
LS
Zhao
Jingjing
J
Zhou
Yuefen
Y
McGuire
Helen M
HM
Xiang
Alan X
AX
Webber
Stephen E
SE
Zhao
Qiang
Q
Han
Qing
Q
Kissinger
Charles R
CR
Lardy
Matthew
M
Gobbi
Alberto
A
Showalter
Richard E
RE
Shah
Amit M
AM
Tsan
Mei
M
Patel
Rupal A
RA
LeBrun
Laurie A
LA
Kamran
Ruhi
R
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Sergeeva
Maria V
MV
Kirkovsky
Leo
L
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011728:Pyridones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase