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 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
Li
Lian-Sheng
LS
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Zhou
Yuefen
Y
Murphy
Douglas E
DE
Stankovic
Nebojsa
N
Zhao
Jingjing
J
Dragovich
Peter S
PS
Bertolini
Thomas
T
Sun
Zhongxiang
Z
Ayida
Benjamin
B
Tran
Chinh V
CV
Ruebsam
Frank
F
Webber
Stephen E
SE
Shah
Amit M
AM
Tsan
Mei
M
Showalter
Richard E
RE
Patel
Rupal
R
Lebrun
Laurie A
LA
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Kamran
Ruhi
R
Brooks
Jennifer
J
Sergeeva
Maria V
MV
Kirkovsky
Leo
L
Zhao
Qiang
Q
Kissinger
Charles R
CR
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D011724:Pyridazines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase