N-(2-hydroxyethyl)-1-((2-methoxy-5-(trifluoromethyl)-pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide | 1615713-84-2

• 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: N-(2-hydroxyethyl)-1-((2-methoxy-5-(trifluoromethyl)-pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
• 英文别名: N-(2-hydroxyethyl)-1-[[2-methoxy-5-(trifluoromethyl)-3-pyridyl]methyl]-6-methyl-pyrrolo[3,2-b]pyridine-3-carboxamide；N-(2-hydroxyethyl)-1-[[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl]-6-methylpyrrolo[3,2-b]pyridine-3-carboxamide
• CAS: 1615713-84-2
• 化学式: C₁₉H₁₉F₃N₄O₃
• 分子量: 408.38
• InChiKey: BWHKHXLTHGBDMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  89.3
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  ethyl 6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate 在 1-甲基吡咯烷 、 1-丙基磷酸酐 、 三乙胺 、 lithium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-(2-hydroxyethyl)-1-((2-methoxy-5-(trifluoromethyl)-pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
  参考文献：
  名称：

  Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents

  摘要：

  In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.

  DOI：

  10.1021/jm500571f

文献信息

• Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
  作者：Pravin S. Shirude、Radha K. Shandil、M. R. Manjunatha、Claire Sadler、Manoranjan Panda、Vijender Panduga、Jitendar Reddy、Ramanatha Saralaya、Robert Nanduri、Anisha Ambady、Sudha Ravishankar、Vasan K. Sambandamurthy、Vaishali Humnabadkar、Lalit K. Jena、Rudrapatna S. Suresh、Abhishek Srivastava、K. R. Prabhakar、James Whiteaker、Robert E. McLaughlin、Sreevalli Sharma、Christopher B. Cooper、Khisi Mdluli、Scott Butler、Pravin S. Iyer、Shridhar Narayanan、Monalisa Chatterji

  DOI：10.1021/jm500571f

  日期：2014.7.10

  In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.