Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. sdsunhee@yahoo.com
Sun Hee
SH
Kim
Martin T
MT
Tran
Frank
F
Ruebsam
Alan X
AX
Xiang
Benjamin
B
Ayida
Helen
H
McGuire
David
D
Ellis
Julie
J
Blazel
Chinh V
CV
Tran
Douglas E
DE
Murphy
Stephen E
SE
Webber
Yuefen
Y
Zhou
Amit M
AM
Shah
Mei
M
Tsan
Richard E
RE
Showalter
Rupal
R
Patel
Alberto
A
Gobbi
Laurie A
LA
LeBrun
Darian M
DM
Bartkowski
Thomas G
TG
Nolan
Daniel A
DA
Norris
Maria V
MV
Sergeeva
Leo
L
Kirkovsky
Qiang
Q
Zhao
Qing
Q
Han
Charles R
CR
Kissinger
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D012367:RNA, Viral / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D013844:Thiazoles; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase