(S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(4-(cyclobutanecarboxamido)-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(4-(cyclobutanecarboxamido)-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
• 英文别名: propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-[4-(cyclobutanecarbonylamino)-2-oxopyrimidin-1-yl]-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• 化学式: C₂₇H₃₆FN₄O₉P
• 分子量: 610.576
• InChiKey: AMSSFUJDKQJMQX-CTWZYUOZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  165
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-氨基-1-((2R,3R,4R,5R)-3-氟-4-羟基-5-(羟基甲基)-3-甲基四氢呋喃-2-基)嘧啶-2(1H)-酮 、 环丁基甲酸 在 N-甲基吗啉 、 叔丁基氯化镁 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(4-(cyclobutanecarboxamido)-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
  参考文献：
  名称：

  Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation

  摘要：

  Resistant HCV variants carrying NSSB S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NSSB polymerase inhibitor. On the basis of the finding that 2'-alpha-F-2'-beta-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N-4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity, The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 mu M) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 mu M) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 mu M) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 mu M) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.

  DOI：

  10.1021/acs.jmedchem.7b00262

文献信息

• Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation
  作者：Le Zhen、Liang Dai、Xiaoan Wen、Lan Yao、Xiaoliang Jin、Xiao-Wen Yang、Wenfeng Zhao、Sheng-Qi Yu、Haoliang Yuan、Guangji Wang、Hongbin Sun

  DOI：10.1021/acs.jmedchem.7b00262

  日期：2017.7.27

  Resistant HCV variants carrying NSSB S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NSSB polymerase inhibitor. On the basis of the finding that 2'-alpha-F-2'-beta-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N-4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity, The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 mu M) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 mu M) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 mu M) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 mu M) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.