title: Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2'-C-methylcytidine.
abstract: In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), and three flaviviruses, namely, yellow fever virus, West Nile virus, and dengue-2 virus. However, pharmacokinetic studies revealed that 2'-C-methylcytidine suffers from a low oral bioavailability. To overcome this limitation, we have synthesized the 3'-O-l-valinyl ester derivative (dihydrochloride form, valopicitabine, NM283) of 2'-C-methylcytidine. We detail herein for the first time the chemical synthesis and physicochemical characteristics of this anti-HCV prodrug candidate, as well as a comparative study of its pharmacokinetic parameters with those of its parent nucleoside analogue, 2'-C-methylcytidine.
authors.affiliation: Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Case Courrier 008, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pierra
authors.forename: Agnès
authors.initials: A
authors.lastname: Amador
authors.forename: Samira
authors.initials: S
authors.lastname: Benzaria
authors.forename: Erika
authors.initials: E
authors.lastname: Cretton-Scott
authors.forename: Marc
authors.initials: M
authors.lastname: D'Amours
authors.forename: John
authors.initials: J
authors.lastname: Mao
authors.forename: Steven
authors.initials: S
authors.lastname: Mathieu
authors.forename: Adel
authors.initials: A
authors.lastname: Moussa
authors.forename: Edward G
authors.initials: EG
authors.lastname: Bridges
authors.forename: David N
authors.initials: DN
authors.lastname: Standring
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Sommadossi
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
authors.forename: Gilles
authors.initials: G
authors.lastname: Gosselin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; C513402:2'-C-methylcytidine; D003562:Cytidine; C506207:valopicitabine