1-(2,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-y)-1H-吡唑-3-羧酸 | 1015765-70-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1-(2,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-y)-1H-吡唑-3-羧酸
• 英文名称: 1-(2,4-dichlorophenyl)-4-methyl-5-(1H-pyrrol-1-y)-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-(2,4-Dichlorophenyl)-4-methyl-5-pyrrol-1-ylpyrazole-3-carboxylic acid
• CAS: 1015765-70-4
• 化学式: C₁₅H₁₁Cl₂N₃O₂
• 分子量: 336.177
• InChiKey: AMSSUKYMIORFDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  60
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-y)-1H-吡唑-3-羧酸 在 N-甲基吗啉 、 氯化亚砜 、 ethylene dichloride hydrochloride 、 1-羟基苯并三唑 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 21.0h， 生成
  参考文献：
  名称：

  探索第一个Rimonabant类似物-阿片肽杂合化合物，作为CB1和阿片受体的二价配体。

  摘要：

  大麻素（CB）和阿片类药物系统均与镇痛，食物摄入，情绪和行为有关。由于在中枢神经系统（CNS）的各个区域中，μ阿片类药物（MOR）和CB1受体共定位，并且它们具有形成异二聚体的能力，因此针对这两个系统的二价配体可能是研究是否存在阿片类药物的良好候选者。在次有效剂量下也可能产生串扰或协同效应。在这项工作中，我们从一小部分新的Rimonabant类似物中选择一种CB1R反向激动剂与阿片样物质Tyr-D-Ala-Gly-Phe-NH2偶联。二价化合物（9）已用于体外结合测定，体内抗伤害感受模型和体外下丘脑灌注试验，以评估神经递质的释放。

  DOI：

  10.1080/14756366.2016.1260565
• 作为产物：
  描述：

  ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以94%的产率得到1-(2,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-y)-1H-吡唑-3-羧酸
  参考文献：
  名称：

  Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides

  摘要：

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.

  DOI：

  10.1021/jm070566z

文献信息

• Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile
  作者：Romano Silvestri、Alessia Ligresti、Giuseppe La Regina、Francesco Piscitelli、Valerio Gatti、Antonella Brizzi、Serena Pasquini、Antonio Lavecchia、Marco Allarà、Noemi Fantini、Mauro Antonio Maria Carai、Ettore Novellino、Giancarlo Colombo、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1016/j.bmc.2009.06.027

  日期：2009.8

  New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB1 receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB1 receptor, with Ki concentrations comparable to the reference compounds 1, 4 and 5, and exhibited

  通过取代先前报道的3-羧酰胺氮上的2,4-二氯苄基和环己基部分，合成了新的取代的1-芳基-5-（1 H-吡咯-1-基）-1 H-吡唑-3-羧酰胺CB 1受体拮抗剂/反向激动剂4和5。几个配体显示了强的亲合性为HCB 1受体，具有ķ我浓度下媲美的参考化合物1，4和5，并显示出CB 1选择性比得上1和2。对接实验和分子动力学（MD）模拟解释了化合物31和37与hCB 1的强结合亲和力。根据我们以前的研究，31和37与K3.28（192）形成H键，这说明对受体无活性状态和反向激动剂活性具有高亲和力。在对大鼠急性给药后发现食物摄入受到抑制，这支持了CB 1选择性化合物4和52充当拮抗剂/反向激动剂的概念。
• Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands
  作者：Romano Silvestri、Alessia Ligresti、Giuseppe La Regina、Francesco Piscitelli、Valerio Gatti、Antonio Lavecchia、Antonella Brizzi、Serena Pasquini、Marco Allarà、Noemi Fantini、Mauro Antonio Maria Carai、Chiara Bigogno、Marco Giulio Rozio、Roberta Sinisi、Ettore Novellino、Giancarlo Colombo、Vincenzo Di Marzo、Giulio Dondio、Federico Corelli

  DOI：10.1016/j.ejmech.2010.09.053

  日期：2010.12

  A series of N-alkyl 1-ary1-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB(1). n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB(1) receptor affinity (compound 24: K-i; = 45.6 nM; 29: K-i = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands. (C) 2010 Elsevier Masson SAS. All rights reserved.
• Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1<i>H</i>-pyrrol-1-yl)-1<i>H</i>-pyrazole-3-carboxamides
  作者：Romano Silvestri、Maria Grazia Cascio、Giuseppe La Regina、Francesco Piscitelli、Antonio Lavecchia、Antonella Brizzi、Serena Pasquini、Maurizio Botta、Ettore Novellino、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1021/jm070566z

  日期：2008.3.1

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
• Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors
  作者：Adriano Mollica、Sveva Pelliccia、Valeria Famiglini、Azzurra Stefanucci、Giorgia Macedonio、Annalisa Chiavaroli、Giustino Orlando、Luigi Brunetti、Claudio Ferrante、Stefano Pieretti、Ettore Novellino、Sandor Benyhe、Ferenc Zador、Anna Erdei、Edina Szucs、Reza Samavati、Szabolcs Dvorácskó、Csaba Tomboly、Rino Ragno、Alexandros Patsilinakos、Romano Silvestri

  DOI：10.1080/14756366.2016.1260565

  日期：2017.1.1

  Cannabinoid (CB) and opioid systems are both involved in analgesia, food intake, mood and behavior. Due to the co-localization of µ-opioid (MOR) and CB1 receptors in various regions of the central nervous system (CNS) and their ability to form heterodimers, bivalent ligands targeting to both these systems may be good candidates to investigate the existence of possible cross-talking or synergistic effects

  大麻素（CB）和阿片类药物系统均与镇痛，食物摄入，情绪和行为有关。由于在中枢神经系统（CNS）的各个区域中，μ阿片类药物（MOR）和CB1受体共定位，并且它们具有形成异二聚体的能力，因此针对这两个系统的二价配体可能是研究是否存在阿片类药物的良好候选者。在次有效剂量下也可能产生串扰或协同效应。在这项工作中，我们从一小部分新的Rimonabant类似物中选择一种CB1R反向激动剂与阿片样物质Tyr-D-Ala-Gly-Phe-NH2偶联。二价化合物（9）已用于体外结合测定，体内抗伤害感受模型和体外下丘脑灌注试验，以评估神经递质的释放。