7-methyl-5-(1-{[3-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine | 1337531-42-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 7-methyl-5-(1-{[3-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• 英文别名: 1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)indolin-1-yl)-2-(3-methoxyphenyl)ethan-1-one；1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-methoxyphenyl)ethanone
• CAS: 1337531-42-6
• 化学式: C₂₄H₂₃N₅O₂
• 分子量: 413.479
• InChiKey: NSTSANFOMJOPFU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  86.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-BOC-5-溴吲哚啉 在 盐酸 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium phosphate monohydrate 、 potassium acetate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 7-methyl-5-(1-{[3-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)

  摘要：

  Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.

  DOI：

  10.1021/jm300713s

文献信息

• Hypoxia‐Activated Prodrugs of PERK Inhibitors
  作者：Lydia P. Liew、Dean C. Singleton、Way W. Wong、Gary J. Cheng、Stephen M. F. Jamieson、Michael P. Hay

  DOI：10.1002/asia.201801826

  日期：2019.4.15

  presents a target for tumour‐selective drug delivery using hypoxia‐activated prodrugs. We designed and prepared hypoxia‐activated prodrugs of modified PERK inhibitors using a 2‐nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction

  肿瘤缺氧在肿瘤进展和对治疗的抗性中起重要作用。在缺氧条件下，未折叠的蛋白质积聚在内质网（ER）中，这种压力通过未折叠的蛋白质应答（UPR）的蛋白激酶R样ER激酶（PERK）信号臂得以缓解。通过PERK激酶抑制剂靶向UPR可抑制肿瘤生长，但也可引起正常组织的机制毒性。低氧提出了使用低氧激活的前药进行肿瘤选择性药物递送的目标。我们使用2-硝基咪唑生物还原触发剂设计并制备了经过修饰的PERK抑制剂的低氧激活前药。新的抑制剂保留了PERK激酶的抑制活性，相应的前药被强烈失活。前药在辐射分解后能够发生分裂，或HCT116细胞的生物还原，以释放其效应器，尽管效率不高。我们检查了低氧HCT116细胞中前药对PERK信号传导的影响。这项研究已经确定了2-取代的氨基甲酸氨基咪唑基前药，具有以低氧选择性方式递送PERK抑制剂的潜力。
• COMPOUNDS AND METHODS FOR TREATING INSULIN RESISTANCE SYNDROME
  申请人：Cohen Stephen Michael

  公开号：US20140227289A1

  公开（公告）日：2014-08-14

  The present invention relates to a method of treating or preventing insulin resistance syndrome in an animal body by administering an inhibitor of protein kinase RNA-like endoplasmic reticulum kinase (PERK) gene, or a functional variant thereof, or an inhibitor of PERK protein or a functional variant thereof or a method of reducing activity of transcription factors of the FOXO family (Foxo 1, 3a, 4 and 6) by administering an inhibitor of protein kinase RNA-like endoplasmic reticulum kinase (PERK) gene, or a functional variant thereof, or an inhibitor of PERK protein or a functional variant thereof. The present invention also relates to different compounds and methods for using PERK gene or PERK protein.

  本发明涉及通过给动物体内注射蛋白激酶RNA样内质网激酶（PERK）基因的抑制剂或其功能变体，或PERK蛋白或其功能变体的抑制剂，或通过给动物体内注射蛋白激酶RNA样内质网激酶（PERK）基因的抑制剂或其功能变体，或PERK蛋白或其功能变体的抑制剂来减少FOXO家族转录因子（Foxo 1、3a、4和6）活性的方法，用于治疗或预防动物体内的胰岛素抵抗综合征。本发明还涉及不同的化合物和使用PERK基因或PERK蛋白的方法。
• CHEMICAL COMPOUNDS
  申请人：Axten Jeffrey Michael

  公开号：US20120077828A1

  公开（公告）日：2012-03-29

  The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R 1 , R 2 , and R 3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代的吲哚啉衍生物。具体而言，本发明涉及按式I所示的化合物：其中R1、R2和R3在此定义。本发明的化合物是PERK的抑制剂，可用于治疗癌症、眼部疾病和与激活的未折叠蛋白质应答途径相关的疾病，如阿尔茨海默病、中风、1型糖尿病帕金森病、亨廷顿病、肌萎缩性侧索硬化、心肌梗死、心血管疾病、动脉硬化和心律失常，更具体地，乳腺癌、结肠癌、胰腺癌和肺癌。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还涉及使用本发明化合物或包含本发明化合物的药物组合物抑制PERK活性和治疗相关疾病的方法。
• US8598156B2
  申请人：——

  公开号：US8598156B2

  公开（公告）日：2013-12-03
• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2011119663A1

  公开（公告）日：2011-09-29

  The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.