DPRE1抑制剂(DPRE1-IN-2) | 1615713-87-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 中文名称: DPRE1抑制剂(DPRE1-IN-2)
• 英文名称: 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-hydroxyethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
• 英文别名: DprE1-IN-2；1-[[6-(dimethylamino)-5-methylpyrimidin-4-yl]methyl]-N-(2-hydroxyethyl)-6-methylpyrrolo[3,2-b]pyridine-3-carboxamide
• CAS: 1615713-87-5
• 化学式: C₁₉H₂₄N₆O₂
• 分子量: 368.439
• InChiKey: BLNAAWXUNQHVNT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  96.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氯-5-甲基-3-硝基吡啶 在 1-甲基吡咯烷 、 铁粉 、 sodium hydride 、 溶剂黄146 、 1-丙基磷酸酐 、 三乙胺 、 lithium chloride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 生成 DPRE1抑制剂(DPRE1-IN-2)
  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

• 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。
• US9163020B2
  申请人：——

  公开号：US9163020B2

  公开（公告）日：2015-10-20
• [EN] AZAINDOLE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING THE SAME<br/>[FR] COMPOSÉS D'AZA-INDOLE, LEUR SYNTHÈSE ET PROCÉDÉS POUR LES UTILISER
  申请人：GLOBAL ALLIANCE FOR TB DRUG DEV

  公开号：WO2015009525A1

  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.
• 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.