A novel class of phosphonate nucleosides. 9-[(1-phosphonomethoxycyclopropyl)methyl]guanine as a potent and selective anti-HBV agent
A novel class of phosphonate nucleosides. 9-[(1-phosphonomethoxycyclopropyl)methyl]guanine as a potent and selective anti-HBV agent
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DOI：
10.1021/jm0305265
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发表时间：
2004-05-20
影响因子：
7.3
通讯作者：
Kim, YZ
中科院分区：
文献类型：
--
作者：
Choi, JR;Cho, DG;Kim, YZ
9-[1-(Phosphonomethoxycyclopropyl)methyl]鸟嘌呤（PMCG, 1）是一类新型膦酸盐核苷的代表，在HepG2 2.2.15细胞原代培养中具有优异的阻断HBV复制的效力（EC50 = 0.5 muM）。在1.0 mM以下的几种人类细胞系中，它没有明显的细胞毒性。在30ma时，它不抑制人类免疫缺陷病毒（HIV-1）或单纯疱疹病毒（HSV-1）的复制。许多1的嘌呤基类似物也表现出对HBV的抑制活性，但在30mum时，嘧啶类似物则没有。1比阳性对照9-[2-（磷新乙氧基）乙基]腺嘌呤（PMEA）强4倍（EC50 = 2.0 muM）。采用钛介导的Kulinkovich环丙化法制备了1的2′位置的特征性环丙基。1被修改为口服候选药物PMCDG Dipivoxil(2)。在一项对感染土拨鼠乙型肝炎病毒（WHBV）的土拨鼠进行的研究中，以每公斤每天5毫克的剂量给药的化合物2显示出极好的疗效。候选药物2已成功完成I期临床试验，目前正在进行疗效评估的II期临床研究。
9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.