Phosphoramidate prodrugs of 2'-C-methylcytidine for therapy of hepatitis C virus infection.
The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
Gardelli
Cristina
C
Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare, P. Angeletti SpA. (IRBM-MRL Rome), Pomezia, Italy. cristina_gardelli@merck.com
Attenni
Barbara
B
Donghi
Monica
M
Meppen
Malte
M
Pacini
Barbara
B
Harper
Steven
S
Di Marco
Annalise
A
Fiore
Fabrizio
F
Giuliano
Claudio
C
Pucci
Vincenzo
V
Laufer
Ralph
R
Gennari
Nadia
N
Marcucci
Isabella
I
Leone
Joseph F
JF
Olsen
David B
DB
MacCoss
Malcolm
M
Rowley
Michael
M
Narjes
Frank
F
D000577:Amides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D010756:Phosphoric Acids / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D011122:Polyphosphates / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011122:Polyphosphates; D011355:Prodrugs; C513402:2'-C-methylcytidine; D003562:Cytidine; C011067:phosphoramidic acid; C005692:triphosphoric acid