Design, synthesis, and antiviral properties of 4'-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479.
A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
Smith
David B
DB
Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Dave.Smith@Roche.com
Martin
Joseph A
JA
Klumpp
Klaus
K
Baker
Stewart J
SJ
Blomgren
Peter A
PA
Devos
Rene
R
Granycome
Caroline
C
Hang
Julie
J
Hobbs
Christopher J
CJ
Jiang
Wen-Rong
WR
Laxton
Carl
C
Le Pogam
Sophie
S
Leveque
Vincent
V
Ma
Han
H
Maile
Graham
G
Merrett
John H
JH
Pichota
Arkadius
A
Sarma
Keshab
K
Smith
Mark
M
Swallow
Steven
S
Symons
Julian
J
Vesey
David
D
Najera
Isabel
I
Cammack
Nick
N
D000998:Antiviral Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000235:genetics*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry; D012313:RNA / Q000737:chemistry; D012263:Ribonucleosides / Q000737:chemistry*; D014529:Uridine; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D009705:Nucleosides; D012263:Ribonucleosides; D003562:Cytidine; D012313:RNA; C508950:4'-azidocytidine; D014529:Uridine