Idenix Pharmaceuticals (IDIX)

[go seek]

Synthesis and Pharmacokinetics of Valopicitabine (NM283), an Efficient Prodrug of the Potent Anti-HCV Agent 2'-C-Methylcytidine.

Author(s)
Pierra C, Amador A, Benzaria S, Cretton-Scott E, D'Amours M, Mao J, Mathieu S, Moussa A, Bridges EG, Standring DN, Sommadossi JP, Storer R, Gosselin G
Institution Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Case Courrier 008, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France, and Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, Massachusetts 02139, and Laboratoires Idenix SARL, Laboratoire de Chimie Médicinale, Cap Gamma, 1682 Rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.

Source J Med Chem 2006 Nov 2; 49(22) :6614-6620.

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.

Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 17064080