The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4'-azidocytidine (R1479).
We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4'-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-muM inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cardiff.ac.uk
Kelleher
Mary Rose
MR
Perrone
Plinio
P
Mulready
Sinead
S
Luoni
Giovanna
G
Daverio
Felice
F
Rajyaguru
Sonal
S
Le Pogam
Sophie
S
Najera
Isabel
I
Martin
Joseph A
JA
Klumpp
Klaus
K
Smith
David B
DB
D000596:Amino Acids / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D008956:Models, Chemical; D011355:Prodrugs; D012093:Replicon / Q000187:drug effects; D013678:Technology, Pharmaceutical / Q000379:methods*; D014779:Virus Replication
D000596:Amino Acids; D000998:Antiviral Agents; D011355:Prodrugs; D003562:Cytidine; C508950:4'-azidocytidine