N-(2-hydroxyethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide | 1494675-86-3

• 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-((6-methoxy-5-methylpyrimidin-4-yl)-methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
• 英文别名: Tba-7371；N-(2-hydroxyethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-6-methylpyrrolo[3,2-b]pyridine-3-carboxamide
• CAS: 1494675-86-3
• 化学式: C₁₈H₂₁N₅O₃
• 分子量: 355.396
• InChiKey: VDRYGTNDKXIPSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.22
• 重原子数：
  26.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  102.16
• 氢给体数：
  2.0
• 氢受体数：
  7.0

安全信息

• 储存条件：
  | 2-8℃ |

制备方法与用途

DprE1-IN-1 是一种有效的 DprE1 抑制剂，其 IC50 值为 10 nM，同时也抑制 PDE6，IC50 值为 6 μM。

反应信息

• 作为产物：
  描述：

  ethyl 3-(dimethylamino)-2-(5-methyl-3-nitropyridin-2-yl)acrylate 在 铁粉 、 potassium carbonate 、 溶剂黄146 、 1-丙基磷酸酐 、 三乙胺 、 lithium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.08h， 生成 N-(2-hydroxyethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
  参考文献：
  名称：

  Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo

  摘要：

  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.

  DOI：

  10.1021/jm401382v

文献信息

• AZAINDOLE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING THE SAME
  申请人：Global Alliance for TB Drug Development

  公开号：US20150025087A1

  公开（公告）日：2015-01-22

  The invention provides compounds of formula (I) and methods of treating a Mycobacterium infection or tuberculosis, or inhibiting DprE1 with the same.

  该发明提供了式（I）的化合物以及用于治疗结核分枝杆菌感染或肺结核，或者用于抑制DprE1的方法。
• 1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis
  作者：Monalisa Chatterji、Radha Shandil、M. R. Manjunatha、Suresh Solapure、Vasanthi Ramachandran、Naveen Kumar、Ramanatha Saralaya、Vijender Panduga、Jitendar Reddy、Prabhakar KR、Sreevalli Sharma、Claire Sadler、Christopher B. Cooper、Khisi Mdluli、Pravin S. Iyer、Shridhar Narayanan、Pravin S. Shirude

  DOI：10.1128/aac.03233-14

  日期：2014.9

  New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β- d -ribose 2′-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro , and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

  摘要 针对耐多药（MDR）和广泛耐药（XDR）结核分枝杆菌的新治疗策略 结核分枝杆菌 迫切需要新的治疗策略来应对全球结核病（TB）的威胁。为此，我们以前曾报道过发现了 1,4-氮杂吲哚，这是一类很有希望的化合物，通过非共价方式抑制癸烯丙基磷酰-β- d -核糖 2′-epimerase (DprE1)。此外，还对该系列进行了优化，以改善其理化性质和在小鼠体内的药代动力学。在此，我们描述了潜在临床候选化合物 2 的候选短名单，该化合物具有强大的细胞活性、类药物特性、在小鼠和大鼠慢性结核感染模型中的疗效以及最小的 体外 安全性。我们还证明，包括化合物 2 在内的这些化合物与其他抗结核药物没有拮抗活性。此外，化合物 2 与 PA824 和 TMC207 在体外实验中显示出协同作用 在体外 而且这种协同作用在 在体内 与 TMC207 的协同作用。据预测，该系列药物在人体中的清除率较低，化合物 2 的预计人体剂量为≤1 克/天。总之，我们的数据表明，1,4-氮杂吲哚（化合物 2）是开发新型抗结核药物的理想候选物质。
• Azaindole compounds, synthesis thereof, and methods of using the same
  申请人：Global Alliance for TB Drug Development

  公开号：US09163020B2

  公开（公告）日：2015-10-20

  The invention provides compounds of formula (I) and methods of treating a Mycobacterium infection or tuberculosis, or inhibiting DprE1 with the same.

  本发明提供了式(I)的化合物以及用于治疗分枝杆菌感染或结核病，或抑制DprE1的方法。
• 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.
• Journal of Medicinal Chemistry 2014, 57, 5728-5737
  作者：

  DOI：——

  日期：——