(2S)-cyclopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphorylamino)propanoate | 1234490-88-0

• 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: (2S)-cyclopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphorylamino)propanoate
• 英文别名: Cyclopentyl (2S)-2-{[{[(2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl]methoxy}(naphthalen-1-yloxy)phosphoryl]amino}propanoate；cyclopentyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate
• CAS: 1234490-88-0
• 化学式: C₃₀H₃₇N₆O₉P
• 分子量: 656.632
• InChiKey: BBKRFCWFPOAKNE-WDNXDORSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  202
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  1-naphthyl(cyclopentoxy-L-alaninyl)phosphorochloridate 、 2'-C-甲基-6-O-甲基鸟苷 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 生成 (2S)-cyclopentyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphorylamino)propanoate
  参考文献：
  名称：

  Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus

  摘要：

  We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modi. cation of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10 nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection. (c) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.06.094

文献信息

• Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus
  作者：Christopher McGuigan、Karolina Madela、Mohamed Aljarah、Arnaud Gilles、Andrea Brancale、Nicola Zonta、Stanley Chamberlain、John Vernachio、Jeff Hutchins、Andrea Hall、Brenda Ames、Elena Gorovits、Babita Ganguly、Alexander Kolykhalov、Jin Wang、Jerry Muhammad、Joseph M. Patti、Geoffrey Henson

  DOI：10.1016/j.bmcl.2010.06.094

  日期：2010.8

  We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modi. cation of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10 nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection. (c) 2010 Elsevier Ltd. All rights reserved.