3-(苯并呋喃-3-基)-4-(5-溴-1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮 | 941575-71-9

• 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: 3-(苯并呋喃-3-基)-4-(5-溴-1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮
• 中文别名: 3-(5-溴-1-甲基-1H-吲哚-3-基)-4-(苯并呋喃-3-基)吡咯-2,5-二酮
• 英文名称: 3-(benzofuran-3-yl)-4-(5-bromo-1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione
• 英文别名: BIP-135；ING-135；3-(benzofuran-3-yl)-4-(5-bromo-1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione；3-(1-benzofuran-3-yl)-4-(5-bromo-1-methylindol-3-yl)pyrrole-2,5-dione
• CAS: 941575-71-9
• 化学式: C₂₁H₁₃BrN₂O₃
• 分子量: 421.25
• InChiKey: QKQJCKAXFJBYKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  64.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(苯并呋喃-3-基)-4-(5-溴-1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮 、 六正丁基二锡 在 四(三苯基膦)钯 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 以20.4%的产率得到3-(benzofuran-3-yl)-4-(1-methyl-5-(tributylstannyl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione
  参考文献：
  名称：

  放射性碘化苯并呋喃-3-基-(indol-3-yl)maleimide 衍生物的合成和初步表征作为潜在的 SPECT 成像探针，用于检测大脑中的糖原合酶激酶-3β (GSK-3β)

  摘要：

  我们报告了两种放射性碘化苯并呋喃-3-基-(indol-3-yl)maleimides, 3-(benzofuran-3-yl)-4-(5-[(125) I]iodo-1 的合成和初步表征-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione ([(125) I]5) 和 3-(5-[(125) I]iodo-1-methyl-1H -indol-3-yl)-4-(6-methoxybenzofuran-3-yl)-1H-pyrrole-2,5-dione ([(125) I]6)，作为第一个针对糖原合酶激酶的潜在 SPECT 成像探针-3β (GSK-3β)。在本研究中，我们使用 (125) I 作为 (123) I 的替代品，因为它易于使用。放射性碘化配体由相应的三丁基锡前体通过碘脱烷基化反应制备，使用过氧化氢作为氧化剂，放射化学产率为 10-30%。体外结合实验表明，这两种化合物对

  DOI：

  10.1002/jlcr.3404
• 作为产物：
  描述：

  5-溴-1-甲基吲哚 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 为溶剂， 生成 3-(苯并呋喃-3-基)-4-(5-溴-1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮
  参考文献：
  名称：

  Structure-Based Design Leads to the Identification of Lithium Mimetics That Block Mania-like Effects in Rodents. Possible New GSK-3β Therapies for Bipolar Disorders

  摘要：

  More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3 beta inhibitors. The best ligand in this series (having a K-i value of 4.6 nM against GSK-3 beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3 beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.

  DOI：

  10.1021/ja068969w

文献信息

• Benzofuran-3-yl(indol-3-yl) Maleimides as Potent GSK3 Inhibitors
  申请人：KOZIKOWSKI Alan P.

  公开号：US20100004308A1

  公开（公告）日：2010-01-07

  Compounds of formula: and pharmaceutically acceptable salts, esters and solvates thereof, where variables are defined in the specification, useful generally as inhibitors of protein kinases and particularly useful for inhibition of GSK-3. Pharmaceutically compositions and medicaments containing a compound of the invention are provided. The invention provides methods of treatment of protein kinase-related disease, disorders or conditions. The invention provides methods of treatment of GSK-3-related diseases, disorders or conditions. More specifically, methods of treatment of bipolar disorder, including mania, schizophrenia, stroke, epilepsy, motor neuron disease, cranial or spinal trauma, neurodegenerative disorders, including multiple sclerosis (MS), Alzheimer's disease, Fragile X syndrome, autism, Huntington's disease, Parkinson's disease, amylotrophic lateral sclerosis (ALS), AIDS-associated dementia, diabetes, particularly type II diabetes, cardiomycete hypertrophy, reperfusion/ischemia, cancer, particularly colorectal cancer, pancreatic cancer, allergies and/or asthma and hair loss or baldness.

  该化合物的公式：以及其药学上可接受的盐、酯和溶剂化物，其中变量在说明书中定义，通常用作蛋白激酶抑制剂，特别是用于抑制GSK-3。提供了含有发明化合物的药学组合物和药物。本发明提供了治疗蛋白激酶相关疾病、紊乱或病况的方法。本发明提供了治疗GSK-3相关疾病、紊乱或病况的方法。更具体地，本发明提供了治疗双相情感障碍、包括躁狂、精神分裂症、中风、癫痫、运动神经元疾病、头部或脊柱创伤、神经退行性疾病、包括多发性硬化症（MS）、阿尔茨海默病、脆性X综合征、自闭症、亨廷顿病、帕金森病、肌萎缩性脊髓侧索硬化症（ALS）、艾滋病相关痴呆、糖尿病，特别是II型糖尿病、心肌肥厚、复灌/缺血、癌症，特别是结肠癌、胰腺癌、过敏和/或哮喘以及脱发或秃发的方法。
• Benzofuran-3-yl(indol-3-yl) maleimides as potent GSK3 inhibitors
  申请人：The Board of Trustees of the University of Illinois

  公开号：US08207216B2

  公开（公告）日：2012-06-26

  Compounds of formula: and pharmaceutically acceptable salts, esters and solvates thereof, where variables are defined in the specification, useful generally as inhibitors of protein kinases and particularly useful for inhibition of GSK-3. Pharmaceutically compositions and medicaments containing a compound of the invention are provided. The invention provides methods of treatment of protein kinase-related disease, disorders or conditions. The invention provides methods of treatment of GSK-3-related diseases, disorders or conditions. More specifically, methods of treatment of bipolar disorder, including mania, schizophrenia, stroke, epilepsy, motor neuron disease, cranial or spinal trauma, neurodegenerative disorders, including multiple sclerosis (MS), Alzheimer's disease, Fragile X syndrome, autism, Huntington's disease, Parkinson's disease, amylotrophic lateral sclerosis (ALS), AIDS-associated dementia, diabetes, particularly type II diabetes, cardiomycete hypertrophy, reperfusion/ischemia, cancer, particularly colorectal cancer, pancreatic cancer, allergies and/or asthma and hair loss or baldness.

  此处提供的化合物公式为：和其药用可接受的盐、酯和溶剂化物，其中变量定义在说明书中，通常用作蛋白激酶抑制剂，特别适用于GSK-3的抑制。本发明提供了含有该化合物的药物组合物和药物。本发明提供了治疗蛋白激酶相关疾病、疾病或病况的方法。本发明提供了治疗GSK-3相关疾病、疾病或病况的方法。更具体地，包括躁狂症、精神分裂症、中风、癫痫、运动神经元疾病、头部或脊柱创伤、神经退行性疾病，包括多发性硬化症（MS）、阿尔茨海默病、脆性X综合症、自闭症、亨廷顿病、帕金森病、肌萎缩性脊髓侧索硬化症（ALS）、艾滋病相关痴呆、糖尿病，特别是2型糖尿病、心肌肥厚、再灌注/缺血、癌症，特别是结肠癌、胰腺癌、过敏和/或哮喘以及脱发或秃发的治疗方法。
• Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof
  申请人：The Broad Institute, Inc.

  公开号：US11203601B2

  公开（公告）日：2021-12-21

  The present disclosure provides compounds of Formula (I), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be useful for inhibiting kinases, e.g., glycogen synthase kinase 3 (GSK3). The provided compounds may be able to selectively inhibit GSK3a, as compared to GSK3P and/or other kinases. The present disclosure further provides pharmaceutical compositions, kits, and methods of use, each of which involve the compounds. The compounds, pharmaceutical compositions, and kits may be useful for treating diseases associated with aberrant activity of GSK3a (e.g., Fragile X syndrome, attention deficit hyperactivity disorder (ADHD), childhood seizure, intellectual disability, diabetes, acute myeloid leukemia (AML), autism, and psychiatric disorder).

  本公开提供了式(I)化合物及其盐类、溶解物、水合物、多晶体、共晶体、同分异构体、立体异构体、同位素标记的衍生物和原药。所提供的化合物可用于抑制激酶，如糖原合酶激酶 3（GSK3）。与 GSK3P 和/或其它激酶相比，所提供的化合物可选择性地抑制 GSK3a。本公开进一步提供了药物组合物、试剂盒和使用方法，其中每一种都涉及这些化合物。这些化合物、药物组合物和试剂盒可用于治疗与 GSK3a 异常活性相关的疾病（如脆性 X 综合征、注意缺陷多动障碍 (ADHD)、儿童癫痫发作、智力障碍、糖尿病、急性髓性白血病 (AML)、自闭症和精神障碍）。
• WO2008/77138
  申请人：——

  公开号：——

  公开（公告）日：——
• 3-BENZOFURANYL-4-INDOLYL MALEIMIDES AS POTENT GSK3 INHIBITORS FOR NEUROGENERATIVE DISORDERS
  申请人：The Board of Trustees of the University of Illinois

  公开号：EP2125683A1

  公开（公告）日：2009-12-02