6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole | 1428958-94-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole
• 英文别名: 6-Methoxy-1-(2-methylsulfonylpyrimidin-4-yl)-2-naphthalen-2-ylbenzimidazole
• CAS: 1428958-94-4
• 化学式: C₂₃H₁₈N₄O₃S
• 分子量: 430.487
• InChiKey: ANCRWOUMLXZUEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  95.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole 在 二氯甲烷 、 三溴化硼 、 甲胺基甲酰氯 、 三甲胺 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 生成 (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)-pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-ylmethylcarbamate
  参考文献：
  名称：

  氨基甲酸酯 JNK3 抑制剂有望有效治疗阿尔茨海默病：小鼠模型体内研究

  摘要：

  我们一直在开发新的 c-Jun N 末端激酶 3 (JNK3) 抑制剂，作为阿尔茨海默病 (AD) 的潜在治疗方法。我们通过药效优化研究鉴定了潜在的JNK3抑制剂，包括苯并咪唑化合物2和3，但它们不可靠的药代动力学特性导致我们开发了氨基甲酸酯抑制剂2h和3h。体外研究验证了氨基甲酸酯抑制剂2h和3h是有效且高度选择性的 JNK3 抑制剂，具有良好的药代动力学特征。口服2h和3hAPP/PS1 和 3xTg AD 小鼠模型的认知功能均得到改善，表明它们有可能有效治疗阿尔茨海默病。特别是，氨基甲酸酯 JNK3 抑制剂3h将 3xTg AD 小鼠模型的认知功能恢复到接近正常水平，并在体内行为评估过程中导致 3xTg-AD 小鼠海马组织中 pTau 减少。我们打算在临床前研究中进一步开发这些氨基甲酸酯 JNK3 抑制剂，作为治疗 AD 的潜在一流疗法。

  DOI：

  10.1021/acs.jmedchem.3c00393
• 作为产物：
  描述：

  4-methoxyphenylene-1,2-diamine dihydrochloride 在 tris-(dibenzylideneacetone)dipalladium(0) 、 BINAP 、 三乙胺 、 sodium t-butanolate 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 14.5h， 生成 6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole
  参考文献：
  名称：

  Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1 H -benzimidazole derivatives as c-Jun N-terminal kinase inhibitors with neuroprotective effects

  摘要：

  1-Heteroaryl-2-aryl-1H-benzimidazole derivatives were synthesized as inhibitors of c-Jun N-terminal kinases, JNK3. Their activities were evaluated through measurement of K-d using SPR, JNK3 kinase assay, and cell-viability of human neuroblastoma cells. Most tested compounds showed high affinity (10 mu M-46 nM) to JNK3. Among them, compound 16f exhibited potent activities (K-d = 46 nM). Especially, 16f was also found to present a potent cell protective effect (IC50 = 1.09 mu M) against toxicity induced by anisomycin, showing a possibility as protective therapeutics in neuronal cell apoptosis. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.02.021

文献信息

• JNK 저해 활성을 갖는 신규한 벤즈이미다졸 유도체 및 이의 용도
  申请人：Industry-University Cooperation Foundation Hanyang University ERICA Campus 한양대학교 에리카산학협력단(120120008551) Corp. No ▼ 131471-0017977BRN ▼134-82-10205

  公开号：KR101840674B1

  公开（公告）日：2018-03-21

  본 발명은 JNK (C-Jun N-terminal kinase) 저해 활성을 갖는 신규한 벤즈이미다졸 유도체 및 이의 용도에 관한 것이다. 본 발명에 따른 신규 벤즈이미다졸유도체 또는 이의 약학적으로 허용가능한 염은 JNK 3 (c-Jun N-terminal kinase 3)에 대한 우수한 저해 활성을 나타내는바, 퇴행성 뇌신경계 질환의 예방 또는 치료에 있어서, 보다 근본적으로 접근하여 타겟 치료할 수 있을 것으로 기대된다.

  本发明涉及具有JNK（C-Jun N末端激酶）抑制活性的新型苯并咪唑衍生物及其用途。根据本发明，新型苯并咪唑衍生物或其药学上可接受的盐表现出对JNK 3（C-Jun N末端激酶3）的优异抑制活性，预计可以更根本地针对治疗退行性脑神经系统疾病进行靶向治疗。
• Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid β-Induced Neurotoxicity in Primary Rat Neurons
  作者：Joonhong Jun、Jihyun Baek、Songyi Yang、Hyungwoo Moon、Hyejin Kim、Hyunwook Cho、Jung-Mi Hah

  DOI：10.3390/ijms222011084

  日期：——

  As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (−10 fold).

  作为MAPK家族的成员，c-Jun-N末端激酶（JNKs）调节细胞凋亡的生物过程。特别是，JNK3亚型在大脑中以高水平明确表达，并参与神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）的发病机制。在这项研究中，我们制备了一系列五种6-二羟基-1H-苯并[d]咪唑作为JNK3抑制剂，发现它们具有作为神经保护剂的潜力。在之前的引物骨架基础上，苯并咪唑基团经过各种芳基和羟基修饰，得到的化合物表现出改进的JNK3抑制活性和选择性。在合成的37个类似物中，（S）-环丙基（3-（（4-（2-（2,3-二氢苯并[b][1,4]二氧杂环己-6-基）-5,6-二羟基-1H-苯并[d]咪唑-1-基）嘧啶-2-基）氨基）哌啶-1-基）甲酮（35b）表现出最高的JNK3抑制作用（IC50 = 9.7 nM），以及对Aβ诱导的神经元细胞死亡的神经保护作用。作为蛋白激酶抑制剂，它还显示出对其他蛋白激酶，包括JNK1（＞1000倍）和JNK2（-10倍）亚型的优异选择性。
• Benzimidazole derivative having JNK inhibitory activity and use thereof
  申请人：INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY ERICA CAMPUS

  公开号：US10781201B2

  公开（公告）日：2020-09-22

  The present invention relates to a novel benzimidazole derivative having JNK (C-Jun N-terminal kinase) inhibitory activity and use thereof. The novel benzimidazole derivative or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity against c-Jun N-terminal kinase 3(JNK 3), and thus it is expected that target therapy can be attained through a more fundamental approach in the prevention or treatment of degenerative brain-nerve system disease.

  本发明涉及一种具有JNK（C-Jun N-末端激酶）抑制活性的新型苯并咪唑衍生物及其用途。根据本发明的新型苯并咪唑衍生物或其药学上可接受的盐对C-Jun N-末端激酶3（JNK 3）具有极佳的抑制活性，因此有望通过更根本的方法实现靶向治疗，预防或治疗退行性脑神经系统疾病。
• NOVEL BENZIMIDAZOLE DERIVATIVE HAVING JNK INHIBITORY ACTIVITY AND USE THEREOF
  申请人：INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY ERICA CAMPUS

  公开号：US20200039959A1

  公开（公告）日：2020-02-06

  The present invention relates to a novel benzimidazole derivative having JNK (C-Jun N-terminal kinase) inhibitory activity and use thereof. The novel benzimidazole derivative or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity against c-Jun N-terminal kinase 3(JNK 3), and thus it is expected that target therapy can be attained through a more fundamental approach in the prevention or treatment of degenerative brain-nerve system disease.