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.
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
David A
DA
Ellis
Julie K
JK
Blazel
Chinh V
CV
Tran
Frank
F
Ruebsam
Douglas E
DE
Murphy
Lian-Sheng
LS
Li
Jingjing
J
Zhao
Yuefen
Y
Zhou
Helen M
HM
McGuire
Alan X
AX
Xiang
Stephen E
SE
Webber
Qiang
Q
Zhao
Qing
Q
Han
Charles R
CR
Kissinger
Matthew
M
Lardy
Alberto
A
Gobbi
Richard E
RE
Showalter
Amit M
AM
Shah
Mei
M
Tsan
Rupal A
RA
Patel
Laurie A
LA
LeBrun
Ruhi
R
Kamran
Darian M
DM
Bartkowski
Thomas G
TG
Nolan
Daniel A
DA
Norris
Maria V
MV
Sergeeva
Leo
L
Kirkovsky
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