N3-(1-adamantyl)-6-methyl-1-pentyl-4-oxo-1,4-dihydropyridine-3-carboxamide | 1256382-84-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N3-(1-adamantyl)-6-methyl-1-pentyl-4-oxo-1,4-dihydropyridine-3-carboxamide
• 英文别名: CB515；N3-(1-adamantyl)-6-methyl-4-oxo-1-pentyl-1,4-dihydropyridine-3-carboxamide；N-(1-adamantyl)-6-methyl-4-oxo-1-pentylpyridine-3-carboxamide
• CAS: 1256382-84-9
• 化学式: C₂₂H₃₂N₂O₂
• 分子量: 356.508
• InChiKey: WCHVNGMNPCXFCG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N3-(1-adamantyl)-6-methyl-1-pentyl-4-oxo-1,4-dihydropyridine-3-carboxamide 、 β-环糊精 在 三乙胺 作用下， 以 aq. phosphate buffer 、 氘代甲醇 、 重水 为溶剂， 生成
  参考文献：
  名称：

  NMR studies of interactions of new CB2 cannabinoid receptor ligands with cyclodextrins hosts. Correlation with micellar electrokinetic chromatography and reversed phase high performance liquid chromatography

  摘要：

  最近发现的三种选择性 CB2 大麻受体配体是很有前途的抗炎药物，但它们的水溶性很低，妨碍了它们的口服给药。从制药的角度来看，环糊精的受欢迎程度在于它们能与水溶性较差的药物相互作用，提高药物的溶解度。在此，我们测试了三种计算选择性 CB2 配体与 β-CD 或 HP-β-CD 复合物稳定性常数的实验方法：核磁共振、胶束电动色谱法和反相高效液相色谱法。在核磁共振研究中，β-CD 的计算 K 值相对较高，介于 1486 和 3571 M-1 之间。HP-β-CD 的 K 值介于 1203 和 2650 M-1 之间。其他两种技术的 K 值较低。在使用 β-CD 进行的 MECK 研究中，K 值介于 308 和 792 M-1 之间；在使用 HP-β-CD 进行的 MECK 研究中，K 值介于 124 和 764 M-1 之间。最后，在与 β-CD 的 RP-HPLC 研究中，它们介于 539 和 1144 M-1 之间，而与 HP-β-CD 则介于 196 和 396 M-1 之间。这些计算常数表明存在络合现象。随后，通过分子建模研究提出了在 β-CD 中加入一种 CB2 配体的模型。

  DOI：

  10.1007/s10847-013-0295-0
• 作为产物：
  描述：

  6-methyl-4-oxo-1-pentyl-1,4-dihydropyridine-3-carboxylic acid 、 盐酸金刚烷胺 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以57%的产率得到N3-(1-adamantyl)-6-methyl-1-pentyl-4-oxo-1,4-dihydropyridine-3-carboxamide
  参考文献：
  名称：

  4-Oxo-1,4-dihydropyridines as Selective CB₂ Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series

  摘要：

  Growing evidence shows that CB2 receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB2 agonists, we describe here the medicinal chemistry approach leading to the development of CB2 receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB2, receptor while showing only modest affinity for the centrally expressed CB1 cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.

  DOI：

  10.1021/jm100286k

文献信息

• 1,4-Dihydropyridine Derivatives and Their Uses
  申请人：Millet Regis

  公开号：US20120149735A1

  公开（公告）日：2012-06-14

  The present invention relates to 1,4-dihydropyridine derivatives of the formula (I) and their uses in the treatment and/or prevention of diseases and disorders directly or indirectly associated with the modification (increase or decrease) of the activity of the cannabinoid receptor 2 (CB2).

  本发明涉及式（I）的1,4-二氢吡啶衍生物及其在治疗和/或预防与大麻素受体2（CB2）的活性调节（增加或减少）直接或间接相关的疾病和障碍方面的用途。
• 1,4-dihydropyridine derivatives and their uses
  申请人：Université de Lille 2 Droit et Santé

  公开号：EP2261211A1

  公开（公告）日：2010-12-15

  The present invention relates to 1,4-dihydropyridine derivatives of the formula (I) and their uses in the treatment and/or prevention of diseases and disorders directly or indirectly associated with the modification (increase or decrease) of the activity of the cannabinoid receptor 2 (CB2).

  本发明涉及式（I）的 1,4-二氢吡啶衍生物及其在治疗和/或预防与大麻素受体 2（CB2）活性改变（增加或降低）直接或间接相关的疾病和失调中的用途。
• 4-Oxo-1,4-dihydropyridines as Selective CB₂ Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series
  作者：Jamal El Bakali、Giulio G. Muccioli、Nicolas Renault、Delphine Pradal、Mathilde Body-Malapel、Madjid Djouina、Laurie Hamtiaux、Virginie Andrzejak、Pierre Desreumaux、Philippe Chavatte、Didier M. Lambert、Régis Millet

  DOI：10.1021/jm100286k

  日期：2010.11.25

  Growing evidence shows that CB2 receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB2 agonists, we describe here the medicinal chemistry approach leading to the development of CB2 receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB2, receptor while showing only modest affinity for the centrally expressed CB1 cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.
• NMR studies of interactions of new CB2 cannabinoid receptor ligands with cyclodextrins hosts. Correlation with micellar electrokinetic chromatography and reversed phase high performance liquid chromatography
  作者：Nathalie Azaroual、Jamal El Bakali、Delphine Broc、Carole Deghaye、Amaury Farce、Philippe Chavatte、Régis Millet、Claude Vaccher、Emmanuelle Lipka-Belloli

  DOI：10.1007/s10847-013-0295-0

  日期：2014.4

  Three selective CB2 cannabinoid receptor ligands have recently been discovered to be promising anti-inflammatory agents but their low water solubility hinder their per os administration. The popularity of the cyclodextrins, from a pharmaceutical standpoint lies on their ability to interact with poorly water-soluble drugs and improve their solubility. Herein, three experimental approaches for calculating the stability constant of complexes between the selective CB2 ligands and either the β-CD or the HP-β-CD, were tested: nuclear magnetic resonance, micellar electrokinetic chromatography and high performance liquid chromatography in reversed phase. In NMR studies the calculated K values were relatively high and were between 1486 and 3571 M−1 with β-CD. With HP-β-CD they were between 1203 and 2650 M−1. Concerning the two others techniques the K values were found lower. In MECK studies with β-CD they were between 308 and 792 M−1 and with HP-β-CD between 124 and 764 M−1. Finally in RP-HPLC studies with β-CD, they were between 539 and 1144 M−1 and with HP-β-CD between 196 and 396 M−1. These calculated constants suggest that a complexation phenomenon occurs. A model for inclusion of one of the CB2 ligands in the β-CD was then proposed from molecular modeling studies.

  最近发现的三种选择性 CB2 大麻受体配体是很有前途的抗炎药物，但它们的水溶性很低，妨碍了它们的口服给药。从制药的角度来看，环糊精的受欢迎程度在于它们能与水溶性较差的药物相互作用，提高药物的溶解度。在此，我们测试了三种计算选择性 CB2 配体与 β-CD 或 HP-β-CD 复合物稳定性常数的实验方法：核磁共振、胶束电动色谱法和反相高效液相色谱法。在核磁共振研究中，β-CD 的计算 K 值相对较高，介于 1486 和 3571 M-1 之间。HP-β-CD 的 K 值介于 1203 和 2650 M-1 之间。其他两种技术的 K 值较低。在使用 β-CD 进行的 MECK 研究中，K 值介于 308 和 792 M-1 之间；在使用 HP-β-CD 进行的 MECK 研究中，K 值介于 124 和 764 M-1 之间。最后，在与 β-CD 的 RP-HPLC 研究中，它们介于 539 和 1144 M-1 之间，而与 HP-β-CD 则介于 196 和 396 M-1 之间。这些计算常数表明存在络合现象。随后，通过分子建模研究提出了在 β-CD 中加入一种 CB2 配体的模型。