5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).
Ruebsam
Frank
F
Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
Tran
Chinh V
CV
Li
Lian-Sheng
LS
Kim
Sun Hee
SH
Xiang
Alan X
AX
Zhou
Yuefen
Y
Blazel
Julie K
JK
Sun
Zhongxiang
Z
Dragovich
Peter S
PS
Zhao
Jingjing
J
McGuire
Helen M
HM
Murphy
Douglas E
DE
Tran
Martin T
MT
Stankovic
Nebojsa
N
Ellis
David A
DA
Gobbi
Alberto
A
Showalter
Richard E
RE
Webber
Stephen E
SE
Shah
Amit M
AM
Tsan
Mei
M
Patel
Rupal A
RA
Lebrun
Laurie A
LA
Hou
Huiying J
HJ
Kamran
Ruhi
R
Sergeeva
Maria V
MV
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Kirkovsky
Leo
L
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D011728:Pyridones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase