--------------------
- Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2 '-C-methylcytidine

Auteur(s): Pierra C, Amador A, Benzaria S, Cretton-Scott E, D'Amours M, Mao J, Mathieu S, Moussa A., Bridges E G, Standring D N, Sommadossi J P, Storer R, Gosselin G.

(Article) Publié: European Journal Of Medicinal Chemistry, vol. 49 p.6614-6620 (2006)


Résumé:

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.



Commentaires: 098WM Times Cited:23 Cited References Count:29