Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides.
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
de Vicente
Javier
J
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. javier.devicente@roche.com
Hendricks
Robert T
RT
Smith
David B
DB
Fell
Jay B
JB
Fischer
John
J
Spencer
Stacey R
SR
Stengel
Peter J
PJ
Mohr
Peter
P
Robinson
John E
JE
Blake
James F
JF
Hilgenkamp
Ramona K
RK
Yee
Calvin
C
Adjabeng
George
G
Elworthy
Todd R
TR
Li
Jim
J
Wang
Beihan
B
Bamberg
Joe T
JT
Harris
Seth F
SF
Wong
April
A
Leveque
Vincent J P
VJ
Najera
Isabel
I
Le Pogam
Sophie
S
Rajyaguru
Sonal
S
Ao-Ieong
Gloria
G
Alexandrova
Ludmila
L
Larrabee
Susan
S
Brandl
Michael
M
Briggs
Andrew
A
Sukhtankar
Sunil
S
Farrell
Robert
R
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase