title: Cyclic phosphoramidates as prodrugs of 2'-C-methylcytidine.
abstract: 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.
authors.affiliation: 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.
authors.forename: Malte
authors.initials: M
authors.lastname: Meppen
authors.forename: Barbara
authors.initials: B
authors.lastname: Pacini
authors.forename: Renzo
authors.initials: R
authors.lastname: Bazzo
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Koeplinger
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Annalise
authors.initials: A
authors.lastname: Di Marco
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fiore
authors.forename: Claudio
authors.initials: C
authors.lastname: Giuliano
authors.forename: Odalys
authors.initials: O
authors.lastname: Gonzalez-Paz
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pucci
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; C513402:2'-C-methylcytidine; D003562:Cytidine