ethyl 1-(6-fluoro-1H-indole-2-carbonyl)piperidine-4-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: ethyl 1-(6-fluoro-1H-indole-2-carbonyl)piperidine-4-carboxylate
• 化学式: C₁₇H₁₉FN₂O₃
• 分子量: 318.348
• InChiKey: LIMHUUBYUPIMOC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  62.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 1-(6-fluoro-1H-indole-2-carbonyl)piperidine-4-carboxylate 在 caesium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成
  参考文献：
  名称：

  Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

  摘要：

  Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV repliton assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain.

  DOI：

  10.1021/jm401330r
• 作为产物：
  描述：

  哌啶-4-甲酸乙酯 、 6-氟吲哚-2-羧酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.33h， 以16%的产率得到ethyl 1-(6-fluoro-1H-indole-2-carbonyl)piperidine-4-carboxylate
  参考文献：
  名称：

  Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

  摘要：

  Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV repliton assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain.

  DOI：

  10.1021/jm401330r

文献信息

• Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication
  作者：Janice A. Sindac、Scott J. Barraza、Craig J. Dobry、Jianming Xiang、Pennelope K. Blakely、David N. Irani、Richard F. Keep、David J. Miller、Scott D. Larsen

  DOI：10.1021/jm401330r

  日期：2013.11.27

  Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV repliton assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain.