ethyl 5-(4-chloro-3-methylphenyl)-1H-pyrazole-3-carboxylate | 1029295-67-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-(4-chloro-3-methylphenyl)-1H-pyrazole-3-carboxylate
• 英文别名: ethyl 3-(4-chloro-3-methylphenyl)-1H-pyrazole-5-carboxylate
• CAS: 1029295-67-7
• 化学式: C₁₃H₁₃ClN₂O₂
• 分子量: 264.711
• InChiKey: WGCJBTUHSSEXIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  55
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 5-(4-chloro-3-methylphenyl)-1H-pyrazole-3-carboxylate 在 氯化亚砜 、 sodium hydride 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 、 mineral oil 为溶剂， 反应 22.67h， 生成 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  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]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)

  摘要：

  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.

  DOI：

  10.1021/jm400070u
• 作为产物：
  描述：

  在 一水合肼 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以49%的产率得到ethyl 5-(4-chloro-3-methylphenyl)-1H-pyrazole-3-carboxylate
  参考文献：
  名称：

  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]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)

  摘要：

  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.

  DOI：

  10.1021/jm400070u

文献信息

• CANNABINOID RECEPTOR TARGETED AGENT
  申请人：Bornhop Darryl J.

  公开号：US20090105128A1

  公开（公告）日：2009-04-23

  Compounds of the following formula: wherein X is H or substituted with with at least one X being substituted; and halo is fluorine, chlorine, bromine, iodine; and stereoisomers and conjugable analogs thereof.
• US8367714B2
  申请人：——

  公开号：US8367714B2

  公开（公告）日：2013-02-05
• [EN] CANNABINOID RECEPTOR TARGETED AGENT<br/>[FR] AGENT CIBLÉ DU RÉCEPTEUR CANNABINOÏDE
  申请人：UNIV VANDERBILT

  公开号：WO2009029727A1

  公开（公告）日：2009-03-05

  A conjugable selective CB2 receptor ligand capable of targeted delivery, allowing for methods of targeted disease imaging and/or targeted disease treatment using a receptor ligand of the present invention. Additional aspects are method of invention is imaging a molecular event comprising administering a conjugate of the present invention.
• 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.