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

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Claire Pierra,^† Agnès Amador,^† Samira Benzaria,^† Erika Cretton-Scott,^‡ Marc D'Amours,^‡ John Mao,^‡ Steven Mathieu,^‡ Adel Moussa,^‡ Edward G. Bridges,^‡ David N. Standring,^‡ Jean-Pierre Sommadossi,^‡ Richard Storer,^§ and Gilles Gosselin*^†

Laboratoire Coopratif IdenixCNRSUniversit Montpellier II, Case Courrier 008, Universit Montpellier II, Place Eugne Bataillon, 34095 Montpellier Cedex 5, France, and Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, Massachusetts 02139, and Laboratoires Idenix SARL, Laboratoire de Chimie Mdicinale, Cap Gamma, 1682 Rue de la Valsire, BP 50001, 34189 Montpellier Cedex 4, France

J. Med. Chem., 2006, 49 (22), pp 6614–6620

DOI: 10.1021/jm0603623

Publication Date (Web): October 6, 2006

†

Université Montpellier II.

‡

Idenix Pharmaceuticals Inc.

Laboratoires Idenix SARL.

Present address: VASTox plc, 91 Milton Park, Abingdon, Oxfordshire, OX14 4RY, U.K.

Corresponding author. Tel: + 33-4-67143855. Fax: + 33-4-67549610. E-mail: gosselin@univ-montp2.fr.

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.

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Published In Issue November 02, 2006
Received March 28, 2006

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Article

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

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Recommend & Share

Related Content

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Optimization of Novel Acyl Pyrrolidine Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase Leading to a Development Candidate

Development and Preliminary Optimization of Indole-N-Acetamide Inhibitors of Hepatitis C Virus NS5B Polymerase

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