title: Phosphoramidate prodrugs of 2'-C-methylcytidine for therapy of hepatitis C virus infection.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare, P. Angeletti SpA. (IRBM-MRL Rome), Pomezia, Italy. cristina_gardelli@merck.com
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Attenni
authors.forename: Monica
authors.initials: M
authors.lastname: Donghi
authors.forename: Malte
authors.initials: M
authors.lastname: Meppen
authors.forename: Barbara
authors.initials: B
authors.lastname: Pacini
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
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: Vincenzo
authors.initials: V
authors.lastname: Pucci
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Nadia
authors.initials: N
authors.lastname: Gennari
authors.forename: Isabella
authors.initials: I
authors.lastname: Marcucci
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
mesh_terms: 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
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011122:Polyphosphates; D011355:Prodrugs; C513402:2'-C-methylcytidine; D003562:Cytidine; C011067:phosphoramidic acid; C005692:triphosphoric acid