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.
Kim
Sun Hee
SH
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. sdsunhee@yahoo.com
Tran
Martin T
MT
Ruebsam
Frank
F
Xiang
Alan X
AX
Ayida
Benjamin
B
McGuire
Helen
H
Ellis
David
D
Blazel
Julie
J
Tran
Chinh V
CV
Murphy
Douglas E
DE
Webber
Stephen E
SE
Zhou
Yuefen
Y
Shah
Amit M
AM
Tsan
Mei
M
Showalter
Richard E
RE
Patel
Rupal
R
Gobbi
Alberto
A
LeBrun
Laurie A
LA
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Sergeeva
Maria V
MV
Kirkovsky
Leo
L
Zhao
Qiang
Q
Han
Qing
Q
Kissinger
Charles R
CR
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