Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones.
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
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
Tracy
Jahari
J
Chin
Elbert
E
Li
Jim
J
Wang
Beihan
B
Bamberg
Joe T
JT
Stephenson
Rebecca
R
Oshiro
Connie
C
Harris
Seth F
SF
Ghate
Manjiri
M
Leveque
Vincent
V
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
Xu
Brian
B
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D011804:Quinolines; D015363:Quinolones; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase