Cyclic phosphoramidates as prodrugs of 2'-C-methylcytidine.
The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2'-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes.
Meppen
Malte
M
Department of Chemistry-Istituto di Ricerche di Biologia Molecolare, P. Angeletti S.p.A. (IRBM-MRL Rome), Via Pontina Km 30.600, 00040 Pomezia, Italy.
Pacini
Barbara
B
Bazzo
Renzo
R
Koch
Uwe
U
Leone
Joseph F
JF
Koeplinger
Kenneth A
KA
Rowley
Michael
M
Altamura
Sergio
S
Di Marco
Annalise
A
Fiore
Fabrizio
F
Giuliano
Claudio
C
Gonzalez-Paz
Odalys
O
Laufer
Ralph
R
Pucci
Vincenzo
V
Narjes
Frank
F
Gardelli
Cristina
C
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006224:Cricetinae; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004355:Drug Stability; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011355:Prodrugs; C513402:2'-C-methylcytidine; D003562:Cytidine