4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile | 136285-23-9

• 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-carbonitrile
• 英文别名: 4’-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile；4'-[(2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-carbonitrile；2-[4-[(2-Propylbenzimidazol-1-yl)methyl]phenyl]benzonitrile
• CAS: 136285-23-9
• 化学式: C₂₄H₂₁N₃
• 分子量: 351.451
• InChiKey: OZDOSPJQDNIROW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  41.6
• 氢给体数：
  0
• 氢受体数：
  2

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-carbonitrile 在 potassium hydroxide 作用下， 以 甲醇 为溶剂， 反应 336.0h， 以11%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：

  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
• 作为产物：
  描述：

  邻苯二胺 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 3.0h， 生成 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
  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

• Benzimidazole derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0425921A1

  公开（公告）日：1991-05-08

  Novel imidazole derivatives of the formula (I): wherein R¹ is an optionally substituted alkyl group, R² and R³ are independently a group capable of forming anion or a group which can be changed thereinto, ring A is benzene ring optionally having, besides the group shown by R², further substituents, and X shows linkage of phenylene group and phenyl group directly or through a spacer whose atomic chain is not more than 2 and a salt thereof, show antagonistic actions to angiotensin II, thus being useful as therapeutics for cardiovascular diseases.

  式(I)的新型咪唑衍生物： 其中，R¹为任选取代的烷基，R²和R³分别为可形成阴离子的基团或可改变其性质的基团，环A为苯环，除R²所示基团外，还可任选具有其他取代基，X为亚苯基和苯基直接连接或通过原子链不超过2的间隔物连接及其盐，这些衍生物具有拮抗血管紧张素II的作用，因此可作为心血管疾病的治疗药物。
• 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.
• Tackling resistance in chronic myeloid leukemia: Novel cell death modulators with improved efficacy
  作者：Anna M. Schoepf、Stefan Salcher、Petra Obexer、Ronald Gust

  DOI：10.1016/j.ejmech.2021.113285

  日期：2021.4
• New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile
  作者：Victoria Obermoser、Margarethe E. Urban、Manuela S. Murgueitio、Gerhard Wolber、Ulrich Kintscher、Ronald Gust

  DOI：10.1016/j.ejmech.2016.08.027

  日期：2016.11

  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.