Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Ruebsam
Frank
F
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
Sun
Zhongxiang
Z
Ayida
Benjamin K
BK
Webber
Stephen E
SE
Zhou
Yuefen
Y
Zhao
Qiang
Q
Kissinger
Charles R
CR
Showalter
Richard E
RE
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
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects*; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase