Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine
Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine
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DOI：
10.1021/jm0603623
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发表时间：
2006-11-02
影响因子：
7.3
通讯作者：
Gosselin, Gilles
中科院分区：
文献类型：
--
作者：
Pierra, Claire;Amador, Agnes;Gosselin, Gilles
在我们寻找新的慢性丙型肝炎治疗剂的过程中，核糖核苷类似物2'-C-甲基胞苷被发现在许多RNA病毒的细胞培养中是一种有效的选择性抑制剂，包括猪瘟病毒牛病毒性腹泻病毒，丙型肝炎病毒（HCV）的替代模型，以及三种黄病毒，即黄热病病毒，西尼罗病毒和登革热-2病毒。然而，药代动力学研究表明，2'- c -甲基胞苷具有较低的口服生物利用度。为了克服这一限制，我们合成了2'- c -甲基胞苷的3'- o - l -缬氨酸酯衍生物（二盐酸形式，valopicitabine, NM283）。本文首次详细介绍了这种抗hcv前药候选药物的化学合成和物理化学特性，并对其与母体核苷类似物2′- c -甲基胞苷的药代动力学参数进行了比较研究。
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.