5-[4-氟-1-[(6-甲基-2-吡啶基)乙酰基]-2,3-二氢-1H-吲哚-5-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1337532-29-2

• 物质功能分类: 生物化工 - 抑制剂 - 细胞凋亡(Apoptosis)
• 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
• 中文名称: 5-[4-氟-1-[(6-甲基-2-吡啶基)乙酰基]-2,3-二氢-1H-吲哚-5-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
• 英文名称: GSK2656157
• 英文别名: 5-{4-fluoro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine；1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoroindolin-1-yl)-2-(6-methylpyridin-2-yl)ethanone；1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(6-methylpyridin-2-yl)ethanone
• CAS: 1337532-29-2
• 化学式: C₂₃H₂₁FN₆O
• 分子量: 416.458
• InChiKey: PRWSIEBRGXYXAJ-UHFFFAOYSA-N

物化性质

• 熔点：
  194-196°C
• 沸点：
  744.6±60.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（加热时浓度为10mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

GSK2656157 是一种ATP竞争性的高选择性PERK抑制剂，在无细胞试验中IC50为0.9 nM, 比作用于一组300种激酶的选择性高500多倍，无细胞试验中其功能不依赖于eIF2α磷酸化。此外，GSK2656157 可减少凋亡并抑制过度的自噬。

靶点

Target	Value
PERK	0.9 nM (Cell-free assay)

体外研究

使用GSK2656157预处理细胞，可以抑制PERK活化，并减少下游底物phospho-eIF2a、ATF4和CHOP的表达，IC50为10-30 nM。通过用1 mM GSK2656157 处理细胞然后进行未诱导的UPR试验，可抑制新合成蛋白的生成。GSK2656157下调了84分之5的UPR相关基因（DDIT3、HERPUD1、PPP1R15A、C/EBP-β和ERN1），下调幅度超过4倍。在没有外源UPR诱导剂存在时，GSK2656157 对细胞生长无显著作用效果，IC50为6-25 mM。因此，GSK2656157 可用来测评PERK在各种生物学背景下的生物学功能。

体内研究

按50 mg/kg剂量口服处理后，8小时后GSK2656157 完全抑制phospho-PERK Thr980。用50 或 150 mg/kg剂量处理小鼠（每天两次），可以抑制四种肿瘤模型的生长，并表现出剂量依赖性作用，在150 mg/kg 剂量下可抑制54-114% 的肿瘤生长。在GSK2656157 抗肿瘤过程中，可能具有改变氨基酸代谢、降低血管密度和血管灌注的潜在机制。此外，GSK2656157 处理小鼠可以抑制多种人类移植瘤的生长。

反应信息

• 作为产物：
  描述：

  4-氟吲哚 在 盐酸 、 4-二甲氨基吡啶 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-溴代丁二酰亚胺(NBS) 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 tri-tert-butylphosphonium tetrafluoroborate 、 potassium acetate 、 sodium cyanoborohydride 、 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-) 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 氯仿 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 104.17h， 生成 5-[4-氟-1-[(6-甲基-2-吡啶基)乙酰基]-2,3-二氢-1H-吲哚-5-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
  参考文献：
  名称：

  Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

  摘要：

  We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasrnic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

  DOI：

  10.1021/ml400228e

文献信息

• 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。
• Chemical compounds
  申请人：Axten Jeffrey Michael

  公开号：US08598156B2

  公开（公告）日：2013-12-03

  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.

  本发明涉及取代的吲哚啉衍生物。具体而言，本发明涉及符合公式I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、眼部疾病以及与激活的未折叠蛋白质反应途径相关的疾病，例如阿尔茨海默病、中风、1型糖尿病、帕金森病、亨廷顿病、肌萎缩侧索硬化、心肌梗死、心血管疾病、动脉粥样硬化和心律失常，更具体地是乳腺癌、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来抑制PERK活性和治疗与其相关的疾病的方法。
• PERK AND IRE-1A INHIBITORS AGAINST NEURODEVELOPMENTAL DISORDERS
  申请人：Université de Liège

  公开号：EP3656382A1

  公开（公告）日：2020-05-27

  The present invention relates to UPR pathway inhibitors, in particular PERK and IRE-1A inhibitors for use in the prevention or treatment of neurodevelopmental disorders, such as microcephaly caused by ZIKV.

  本发明涉及 UPR 通路抑制剂，特别是 PERK 和 IRE-1A 抑制剂，用于预防或治疗神经发育障碍，如 ZIKV 引起的小头畸形。
• CELL STABILIZATION
  申请人：Biomatrica, Inc.

  公开号：EP3007556B1

  公开（公告）日：2020-05-20