Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).
Ruebsam
Frank
F
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
Webber
Stephen E
SE
Tran
Martin T
MT
Tran
Chinh V
CV
Murphy
Douglas E
DE
Zhao
Jingjing
J
Dragovich
Peter S
PS
Kim
Sun Hee
SH
Li
Lian-Sheng
LS
Zhou
Yuefen
Y
Han
Qing
Q
Kissinger
Charles R
CR
Showalter
Richard E
RE
Lardy
Matthew
M
Shah
Amit M
AM
Tsan
Mei
M
Patel
Rupal
R
Lebrun
Laurie A
LA
Kamran
Ruhi
R
Sergeeva
Maria V
MV
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Kirkovsky
Leo
L
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D011724:Pyridazines; D011758:Pyrroles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase