methyl 1-(4-fluorobenzyl)-3-((2-(morpholin-4-yl)ethyl)carbamoyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | 1261531-19-4

• 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: methyl 1-(4-fluorobenzyl)-3-((2-(morpholin-4-yl)ethyl)carbamoyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
• CAS: 1261531-19-4
• 化学式: C₂₃H₂₅FN₄O₄
• 分子量: 440.474
• InChiKey: VBLJCIJUTCYXHI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.07
• 重原子数：
  32.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  85.69
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  methyl 1-(4-fluorobenzyl)-3-((2-(morpholin-4-yl)ethyl)carbamoyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate 、 N-甲基羟胺盐酸盐 在 sodium tert-pentoxide 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 1.17h， 以50%的产率得到1-(4-fluorobenzyl)-N5-hydroxy-N5-methyl-N3-(2-morpholin-4-ylethyl)-1H-pyrrolo[2,3-c]pyridine-3,5-dicarboxamide
  参考文献：
  名称：

  Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

  摘要：

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.10.022
• 作为产物：
  描述：

  N-(2-氨基乙基)吗啉 、 1-(4-fluorobenzyl)-5-(methoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid 在 N-甲基吗啉 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以99%的产率得到methyl 1-(4-fluorobenzyl)-3-((2-(morpholin-4-yl)ethyl)carbamoyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
  参考文献：
  名称：

  Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

  摘要：

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.10.022