Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2'-C-methylcytidine.
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.
Pierra
Claire
C
Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Case Courrier 008, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
Amador
Agnès
A
Benzaria
Samira
S
Cretton-Scott
Erika
E
D'Amours
Marc
M
Mao
John
J
Mathieu
Steven
S
Moussa
Adel
A
Bridges
Edward G
EG
Standring
David N
DN
Sommadossi
Jean-Pierre
JP
Storer
Richard
R
Gosselin
Gilles
G
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
D000998:Antiviral Agents; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; C513402:2'-C-methylcytidine; D003562:Cytidine; C506207:valopicitabine