4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid | 133141-63-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid
• 英文别名: 4'-[(2-n-Propyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid；2-[4-[(2-propylbenzimidazol-1-yl)methyl]phenyl]benzoic acid
• CAS: 133141-63-6
• 化学式: C₂₄H₂₂N₂O₂
• 分子量: 370.451
• InChiKey: KZUDZUZMYZXWMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氯化铵 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.36h， 以59%的产率得到4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbamide
  参考文献：
  名称：

  使用非细胞毒性细胞死亡调节剂克服慢性粒细胞性白血病细胞对伊马替尼的耐药性。

  摘要：

  最近的研究检查了通过与过氧化物酶体增殖物激活受体γ（PPARγ）配体联合治疗克服慢性粒细胞白血病（CML）患者伊马替尼耐药的可能性。吡格列酮是一种完整的PPARγ激动剂，通过逐渐消除残留的CML干细胞池，提高了患者的生存率。为了评估PPARγ激动剂的药理学特征对规避耐药性的重要性，部分PPARγ激动剂4'-（（（2-丙基-1H-苯并[d]咪唑-1-基）甲基]-[1,1]研究了替米沙坦衍生的'-联苯基] -2-羧酸和其他相关衍生物。带有[1,1'-联苯] -2-羧酰胺部分的4-取代的苯并咪唑衍生物使K562耐药细胞对伊马替尼治疗敏感。尤其是衍生物18a-f，在10μM时不会激活PPARγ超过40％的细胞，从而恢复了伊马替尼在这些细胞中的细胞毒性。细胞死亡调节特性高于吡格列酮。有趣的是，所有新化合物对非耐药性和耐药性细胞均无细胞毒性。他们仅与伊马替尼联用才发挥抗肿瘤作用。

  DOI：

  10.1016/j.ejmech.2019.111748
• 作为产物：
  描述：

  4'-甲基联苯-2-羧酸 在 N-溴代丁二酰亚胺(NBS) 、 硫酸 、 sodium hydride 、 sodium hydroxide 、 过氧化苯甲酰 作用下， 以 甲醇 、 四氯化碳 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 24.0h， 生成 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid
  参考文献：
  名称：

  New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile

  摘要：

  In previous studies, the 4'-((2-propyl-1H-benzo[d]imidazol-1-yemethyl)-[1,1'-biphenyl]-2-carboxylic acid was identified as pharmacophoric core for PPAR gamma activation. In this structure-activity relationship study the C2-alkyl chain was elongated and the 2-COOH group was changed to a carbamide/carbonitrile or shifted to the 3- or 4-position. Furthermore, the benzo[d]imidazole was exchanged by 2,3dihydrobenzo[d]thiazole or 1H-indole. C2-propyl derivatives showed the profile of partial agonists, while elongation of the C2-chain to that of an n-heptyl group or a 4-COOH shift changed the pharmacological profile to that of a potent full agonist. This finding can be explained by binding to the LBD in different ligand conformations. Two anchoring points (Tyr473 and Arg288) exist in the LBD, which have to be contacted to achieve receptor activation. In a crystal violet chemosensitivity assay using COS-7 cells and LNCaP cells expressing PPAR gamma only the carbamide derivatives influenced the cell growth, independently on the presence of the PPAR gamma. Therefore, receptor mediated cytotoxicity can be excluded. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.027

文献信息

• Synthesis and Characterization of Telmisartan‐Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia
  作者：Anna M. Schoepf、Stefan Salcher、Verena Hohn、Florina Veider、Petra Obexer、Ronald Gust

  DOI：10.1002/cmdc.202000092

  日期：2020.6.17

  New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator‐activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death‐modulating effects

  根除慢性粒细胞白血病 (CML) 中癌症干细胞的新策略包括伊马替尼与过氧化物酶体增殖物激活受体 γ (PPARγ) 配体的组合。最近，我们发现 PPARγ 部分激动剂替米沙坦是对伊马替尼治疗耐药的 K562 CML 细胞的有效敏化剂。在此，杂环核心对替米沙坦衍生铅 4'-((2-丙基-1 H-苯并[ d ]咪唑-1-基)甲基)-[1,1研究了'-联苯]-2-羧酸( 3 b )。受 HYL-6d 和选择性 PPARγ 配体 VSP-51 药效学的启发，苯并咪唑被咔唑或吲哚核心取代。结果表明 PPARγ 激活与耐药 CML 细胞对伊马替尼的敏感性之间没有相关性。咔唑或吲哚的 2-COOH 衍生物对 PPARγ 的活性较低，而苯并咪唑则显示出 60-100% 的活化率。在2-CO 2 CH 3衍生物中，只有铅的酯( 2b )轻微激活PPARγ。进一步观察到这种非细胞毒性2b 的致敏作用（80%
• Benzimidazoles and medicaments containing these compounds
  申请人：Dr. Karl Thomae GmbH

  公开号：US05541229A1

  公开（公告）日：1996-07-30

  The invention relates to benzimidazoles of the formula ##STR1## in which R.sub.1 to R.sub.2 are as defined in claim 1, 1 and 3 isomer mixtures thereof and addition salts thereof which have valuable properties. In particular, the novel compounds are angiotensin II antagonists.

  该发明涉及公式##STR1##中的苯并咪唑，其中R.sub.1至R.sub.2如权利要求书中定义，1和3为其异构体混合物及其盐，具有有价值的性质。特别是，这些新化合物是血管紧张素II拮抗剂。
• Benzimidazoles, medicaments containing these compounds and processes for
  申请人：Karl Thomae GmbH

  公开号：US05864043A1

  公开（公告）日：1999-01-26

  The invention relates to benzimidazoles of the formula ##STR1## in which R.sub.1 to R.sub.4 are as defined in claim 1, 1 and 3 isomer mixtures thereof and addition salts thereof which have valuable properties. In particular, the novel compounds are angiotensin II antagonists.

  本发明涉及式为##STR1##的苯并咪唑，其中R.sub.1至R.sub.4如权利要求1所定义，1和3的异构体混合物及其加合盐具有有价值的性质。特别是，这些新型化合物是血管紧张素II受体拮抗剂。
• 一种抗神经炎性化合物及其制备方法和医药用途
  申请人：中国药科大学

  公开号：CN114262299B

  公开（公告）日：2023-08-22

  本发明公开了一种抗神经炎性化合物及其制备方法和医药用途，具有通式I或通式Ⅱ所示的结构；抗神经炎性化合物为含有替米沙坦和芳香开窍药物的结构骨架，及其各自的类似物；替米沙坦能够改善神经炎症和缺血性脑损伤，芳香开窍药物具有促进其他药物入脑的能力。本发明的抗神经炎性化合物可通过减少异常的非磷酸化神经丝蛋白、上调髓鞘碱性蛋白和显著减轻少突胶质细胞损伤，显著保护脑卒中后的脑白质完整性；本发明的抗神经炎性化合物可广泛应用于制备缺血性中风和其他与神经炎症介导的白质损伤相关的神经系统疾病的药物。
• Characterization of new PPARγ agonists: Benzimidazole derivatives—importance of positions 5 and 6, and computational studies on the binding mode
  作者：Matthias Goebel、Gerhard Wolber、Patrick Markt、Bart Staels、Thomas Unger、Ulrich Kintscher、Ronald Gust

  DOI：10.1016/j.bmc.2010.06.102

  日期：2010.8

  In this and previous studies we investigated the importance of partial structures of Telmisartan on PPAR gamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl) methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d] imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPAR gamma DEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPAR gamma activation. An enhanced effect on PPAR gamma activation could be observed if lipophilic moieties are introduced in these positions. 4 '-[(2-Propyl-1H-naphtho[2,3-d] imidazol-1-yl) methyl] biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC50 of 0.26 mu M and the profile of a full agonist.Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments. (C) 2010 Elsevier Ltd. All rights reserved.