4-methyl-1,5-diphenyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide | 1428261-53-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-methyl-1,5-diphenyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide
• 英文别名: 4-methyl-1,5-diphenyl-N-piperidin-1-ylpyrazole-3-carboxamide
• CAS: 1428261-53-3
• 化学式: C₂₂H₂₄N₄O
• 分子量: 360.459
• InChiKey: ATDCKTKMKBPZFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  ethyl 4-methyl-1,5-diphenyl-1H-pyrazole-3-carboxylate 在 氯化亚砜 、 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 乙醇 、 氯仿 、 甲苯 为溶剂， 反应 18.5h， 生成 4-methyl-1,5-diphenyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model

  摘要：

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.07.054

文献信息

• Novel antiobesity agents: Synthesis and pharmacological evaluation of analogues of Rimonabant and of LH21
  作者：Mario Alvarado、Juan Decara、María Jesús Luque、Laura Hernandez-Folgado、María Gómez-Cañas、María Gómez-Ruiz、Javier Fernández-Ruiz、José Elguero、Nadine Jagerovic、Antonia Serrano、Pilar Goya、Fernando Rodríguez de Fonseca

  DOI：10.1016/j.bmc.2013.01.055

  日期：2013.4

  Searching for novel antiobesity agents, a series of cannabinoid LH21 and of Rimonabant-fatty acid amide analogues have been prepared. Synthesis of pyrazoles 2a–2c was achieved by a two steps simple methodology via α,β-unsaturated ketones. Carboxamides 8a–8h were obtained in good yields from esters 7a–7c by a one-pot procedure which takes place under mild conditions. New compounds have been evaluated in

  为了寻找新型的抗肥胖药，已经制备了一系列大麻素LH21和利莫那班-脂肪酸酰胺类似物。吡唑2a – 2c的合成是通过两步简单的方法，通过α，β-不饱和酮实现的。通过在温和条件下进行的一锅法操作，从酯7a - 7c中以高收率获得了羧酰胺8a - 8h。已经在体内评估了新化合物作为厌食药的作用。他们中的一些人表现出令人感兴趣的特性，其通过不涉及内源性大麻素系统的机制减少了大鼠的食物摄入。
• Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model
  作者：Eduardo Hernández-Vázquez、Rodrigo Aguayo-Ortiz、Juan José Ramírez-Espinosa、Samuel Estrada-Soto、Francisco Hernández-Luis

  DOI：10.1016/j.ejmech.2013.07.054

  日期：2013.11

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.