| 1494676-29-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• CAS: 1494676-29-7
• 化学式: C₁₉H₂₃N₅O₂
• 分子量: 353.424
• InChiKey: VIVYWQAWQKDYON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.73
• 重原子数：
  26.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  73.14
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  在 lithium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 生成 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid
  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
• 作为产物：
  描述：

  ethyl 2-(5-methyl-3-nitropyridin-2-yl)acetate 在 铁粉 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  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

• Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>
  作者：Pravin S. Shirude、Radha Shandil、Claire Sadler、Maruti Naik、Vinayak Hosagrahara、Shahul Hameed、Vikas Shinde、Chandramohan Bathula、Vaishali Humnabadkar、Naveen Kumar、Jitendar Reddy、Vijender Panduga、Sreevalli Sharma、Anisha Ambady、Naina Hegde、James Whiteaker、Robert E. McLaughlin、Humphrey Gardner、Prashanti Madhavapeddi、Vasanthi Ramachandran、Parvinder Kaur、Ashwini Narayan、Supreeth Guptha、Disha Awasthy、Chandan Narayan、Jyothi Mahadevaswamy、KG Vishwas、Vijaykamal Ahuja、Abhishek Srivastava、KR Prabhakar、Sowmya Bharath、Ramesh Kale、Manjunatha Ramaiah、Nilanjana Roy Choudhury、Vasan K. Sambandamurthy、Suresh Solapure、Pravin S. Iyer、Shridhar Narayanan、Monalisa Chatterji

  DOI：10.1021/jm401382v

  日期：2013.12.12

  We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-beta-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.