1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-(3-(morpholin-4-yl)propyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide | 1261531-55-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-(3-(morpholin-4-yl)propyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide
• 英文别名: 1-[(4-fluorophenyl)methyl]-N-hydroxy-N-methyl-3-(3-morpholinopropyl)pyrrolo[2,3-c]pyridine-5-carboxamide；1-[(4-fluorophenyl)methyl]-N-hydroxy-N-methyl-3-(3-morpholin-4-ylpropyl)pyrrolo[2,3-c]pyridine-5-carboxamide
• CAS: 1261531-55-8
• 化学式: C₂₃H₂₇FN₄O₃
• 分子量: 426.491
• InChiKey: XLPCZIBBSFMJSC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  70.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(4-fluorobenzyl)-3-(3-(morpholin-4-yl)propyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 、 N-甲基羟胺盐酸盐 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， 以79%的产率得到1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-(3-(morpholin-4-yl)propyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide
  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

文献信息

• Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK
  作者：Steven P. Tanis、Michael B. Plewe、Ted W. Johnson、Scott L. Butler、Deepak Dalvie、Dorothy DeLisle、Klaus R. Dress、Qiyue Hu、Buwen Huang、Jon E. Kuehler、Atsuo Kuki、Wen Liu、Qinghai Peng、Graham L. Smith、Jim Solowiej、Khanh T. Tran、Hai Wang、Anle Yang、Chunfeng Yin、Xiaoming Yu、Junhu Zhang、Huichun Zhu

  DOI：10.1016/j.bmcl.2010.10.022

  日期：2010.12

  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.