Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids.
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
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
Zhao
Junping
J
Elworthy
Todd R
TR
Tracy
Jahari
J
Chin
Elbert
E
Li
Jim
J
Lui
Al
A
Wang
Beihan
B
Oshiro
Connie
C
Harris
Seth F
SF
Ghate
Manjiri
M
Leveque
Vincent J P
VJ
Najera
Isabel
I
Le Pogam
Sophie
S
Rajyaguru
Sonal
S
Ao-Ieong
Gloria
G
Alexandrova
Ludmila
L
Fitch
Bill
B
Brandl
Michael
M
Masjedizadeh
Mohammad
M
Wu
Shao-Yong
SY
de Keczer
Steve
S
Voronin
Tatyana
T
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D011760:Pyrrolidinones; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C009435:tetramic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase