Pierra Claire, Amador Agnès, Benzaria Samira, Cretton-Scott Erika, D'Amours Marc, Mao John, Mathieu Steven, Moussa Adel, Bridges Edward G, Standring David N, Sommadossi Jean-Pierre, Storer Richard, Gosselin Gilles
Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Case Courrier 008, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
J Med Chem. 2006 Nov 2;49(22):6614-20. doi: 10.1021/jm0603623.
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.
在我们寻找抗慢性丙型肝炎新治疗药物的过程中，发现一种核糖核苷类似物2'-C-甲基胞苷在细胞培养中对多种RNA病毒具有强效且选择性的抑制作用，这些病毒包括瘟病毒属的牛病毒性腹泻病毒（丙型肝炎病毒（HCV）的替代模型）以及三种黄病毒，即黄热病毒、西尼罗河病毒和登革2型病毒。然而，药代动力学研究表明，2'-C-甲基胞苷的口服生物利用度较低。为克服这一局限性，我们合成了2'-C-甲基胞苷的3'-O-L-缬氨酰酯衍生物（二盐酸盐形式，缬更昔洛韦，NM283）。本文首次详细介绍了这种抗HCV前药候选物的化学合成及物理化学特性，以及对其药代动力学参数与母体核苷类似物2'-C-甲基胞苷的药代动力学参数的比较研究。
