Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda6-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: exploration of 7'-substitution of benzothiadiazine.
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure-activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed.
Zhou
Yuefen
Y
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Webber
Stephen E
SE
Murphy
Douglas E
DE
Li
Lian-Sheng
LS
Dragovich
Peter S
PS
Tran
Chinh V
CV
Sun
Zhongxiang
Z
Ruebsam
Frank
F
Shah
Amit M
AM
Tsan
Mei
M
Showalter
Richard E
RE
Patel
Rupal
R
Li
Bin
B
Zhao
Qiang
Q
Han
Qing
Q
Hermann
Thomas
T
Kissinger
Charles R
CR
Lebrun
Laurie
L
Sergeeva
Maria V
MV
Kirkovsky
Leo
L
D001581:Benzothiadiazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase