4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase.
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
Ellis
David A
DA
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Blazel
Julie K
JK
Webber
Stephen E
SE
Tran
Chinh V
CV
Dragovich
Peter S
PS
Sun
Zhongxiang
Z
Ruebsam
Frank
F
McGuire
Helen M
HM
Xiang
Alan X
AX
Zhao
Jingjing
J
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
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Sergeeva
Maria V
MV
Kirkovsky
Leo
L
D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000201:enzymology*; D008956:Models, Chemical; D008968:Molecular Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
D011724:Pyridazines; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase