Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 2: Variation of the 2- and 6-pyridazinone substituents.
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.
Zhou
Yuefen
Y
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Li
Lian-Sheng
LS
Dragovich
Peter S
PS
Murphy
Douglas E
DE
Tran
Chinh V
CV
Ruebsam
Frank
F
Webber
Stephen E
SE
Shah
Amit M
AM
Tsan
Mei
M
Averill
April
A
Showalter
Richard E
RE
Patel
Rupal
R
Han
Qing
Q
Zhao
Qiang
Q
Hermann
Thomas
T
Kissinger
Charles R
CR
Lebrun
Laurie
L
Sergeeva
Maria V
MV
D018360:Crystallography, X-Ray; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011724:Pyridazines; D013829:Thiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase