5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrrole-3-carbaldehyde | 1449692-04-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrrole-3-carbaldehyde
• 英文别名: 5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-1H-pyrrole-3-carbaldehyde；5-(4-Chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]pyrrole-3-carbaldehyde；5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]pyrrole-3-carbaldehyde
• CAS: 1449692-04-9
• 化学式: C₂₀H₁₈ClNO
• 分子量: 323.822
• InChiKey: ZCBJNHJBCCHTSV-UHFFFAOYSA-N

物化性质

• 沸点：
  471.1±45.0 °C(predicted)
• 密度：
  1.13±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  22
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  1-(4-氯苯基)哌嗪 、 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrrole-3-carbaldehyde 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 5.0h， 以38%的产率得到1-{[5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-1H-pyrrol-3-yl]methyl}-4-(4-chlorophenyl)piperazine
  参考文献：
  名称：

  Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB 2 receptor antagonists

  摘要：

  During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (K-i in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [S-35]-GTP gamma S binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.06.057
• 作为产物：
  描述：

  4-氯-3-甲基苯乙酮 在 三乙烯二胺 、 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 盐酸羟胺 、 水 、 sodium acetate 、 sodium hydride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 31.42h， 生成 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrrole-3-carbaldehyde
  参考文献：
  名称：

  Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB 2 receptor antagonists

  摘要：

  During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (K-i in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [S-35]-GTP gamma S binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.06.057

文献信息

• The Importance of Hydrogen Bonding and Aromatic Stacking to the Affinity and Efficacy of Cannabinoid Receptor CB₂ Antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-<i>N</i>-[(1<i>S</i>,2<i>S</i>,4<i>R</i>)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)
  作者：Evangelia Kotsikorou、Frank Navas、Michael J. Roche、Anne F. Gilliam、Brian F. Thomas、Herbert H. Seltzman、Pritesh Kumar、Zhao-Hui Song、Dow P. Hurst、Diane L. Lynch、Patricia H. Reggio

  DOI：10.1021/jm400070u

  日期：2013.9.12

  Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphe nyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicydo [2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB2 inactive state model that were then tested via compound synthesis, binding, and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenthyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogues.
• Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB 2 receptor antagonists
  作者：Giulio Ragusa、María Gómez-Cañas、Paula Morales、Dow P. Hurst、Francesco Deligia、Ruth Pazos、Gerard A. Pinna、Javier Fernández-Ruiz、Pilar Goya、Patricia H. Reggio、Nadine Jagerovic、Moisés García-Arencibia、Gabriele Murineddu

  DOI：10.1016/j.ejmech.2015.06.057

  日期：2015.8

  During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (K-i in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [S-35]-GTP gamma S binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model. (C) 2015 Elsevier Masson SAS. All rights reserved.