1-(2,4-difluorophenyl)-4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylic acid | 1490390-45-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(2,4-difluorophenyl)-4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylic acid
• CAS: 1490390-45-8
• 化学式: C₁₈H₁₁F₅N₂O₂
• 分子量: 382.29
• InChiKey: JRAAZNVWEFGHGY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.84
• 重原子数：
  27.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  55.12
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  1-(2,4-difluorophenyl)-4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylic acid 在 氯化亚砜 、 N,N-二异丙基乙胺 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 6.5h， 生成 1-(2,4-difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-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
• 作为产物：
  描述：

  2,4-二氟苯肼 在 potassium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 乙醇 、 甲基环己烷 为溶剂， 反应 31.0h， 生成 1-(2,4-difluorophenyl)-4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylic acid
  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

• 1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies
  作者：Eduardo Hernández-Vázquez、Romina Castañeda-Arriaga、Juan José Ramírez-Espinosa、Omar Noel Medina-Campos、Francisco Hernández-Luis、José Pedraza Chaverri、Samuel Estrada-Soto

  DOI：10.1016/j.ejmech.2015.06.010

  日期：2015.7

  Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values. (C) 2015 Elsevier Masson SAS. All rights reserved.
• ENP11, a potential CB1R antagonist, induces anorexia in rats
  作者：Mónica Méndez-Díaz、Octavio Amancio-Belmont、Eduardo Hernández-Vázquez、Alejandra E. Ruiz-Contreras、Francisco Hernández-Luis、Oscar Prospéro-García

  DOI：10.1016/j.pbb.2015.06.007

  日期：2015.8

  Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0 mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats.Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0 mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4 h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control.We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature. (C) 2015 Elsevier Inc. All rights reserved.