3,3-dimethyl-1-(4-{3-[1-(3-nitropyridin-2-yl)piperidin-4-ylidene]prop-1-yn-1-yl}phenyl)azetidin-2-one | 1107619-02-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: 3,3-dimethyl-1-(4-{3-[1-(3-nitropyridin-2-yl)piperidin-4-ylidene]prop-1-yn-1-yl}phenyl)azetidin-2-one
• 英文别名: 3,3-Dimethyl-1-{4-[1-(3-nitropyridin-2-yl)piperidin-4-ylidene]prop-1-ynylphenyl}azetidin-2-one；3,3-Dimethyl-1-[4-[3-[1-(3-nitropyridin-2-yl)piperidin-4-ylidene]prop-1-ynyl]phenyl]azetidin-2-one
• CAS: 1107619-02-2
• 化学式: C₂₄H₂₄N₄O₃
• 分子量: 416.48
• InChiKey: VRZDSHWONUJHHO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  82.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-nitro-2-{4-[3-(trimethylsilyl)prop-2-yn-1-ylidene]piperidin-1-yl}pyridine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 四丁基氟化铵 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 3,3-dimethyl-1-(4-{3-[1-(3-nitropyridin-2-yl)piperidin-4-ylidene]prop-1-yn-1-yl}phenyl)azetidin-2-one
  参考文献：
  名称：

  Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

  摘要：

  Metabotropic glutamate receptor 5 (mGlu(5)) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu(5). A homology model of the 7TM receptor domain built on the crystal structure of the mGlu(1) template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu(5) crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu(5) were extended to include important non-aryl alkyne mGlu(5) NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu(5) and may facilitate the design of new modulators for this class of receptors. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.008

文献信息

• NOVEL HETEROCYCLIC DERIVATIVES AS M-GLU5 ANTAGONISTS
  申请人：Leonardi Amedeo

  公开号：US20090042841A1

  公开（公告）日：2009-02-12

  This invention relates to novel heterocyclic compounds having selective affinity for the mGlu5 subtype of metabotropic receptors, pharmaceutical compositions thereof and uses for such compounds and compositions in the treatment of lower urinary tract disorders, such as neuromuscular dysfunction of the lower urinary tract, and in the treatment of migraine and gastroesophagael reflux disease (GERD).

  本发明涉及一种新型杂环化合物，其具有选择性亲和力，适用于代谢型受体mGlu5亚型，以及该类化合物的制药组合物及其在治疗下尿路障碍（例如下尿路神经肌肉功能障碍）、偏头痛和胃食管反流病（GERD）方面的用途。
• NOVEL HETEROCYCLIC COMPOUNDS AS MGLU5 ANTAGONISTS
  申请人：Recordati Ireland Limited

  公开号：EP2178858B1

  公开（公告）日：2011-12-28
• US8518916B2
  申请人：——

  公开号：US8518916B2

  公开（公告）日：2013-08-27
• [EN] NOVEL HETEROCYCLIC COMPOUNDS AS MGLU5 ANTAGONISTS<br/>[FR] NOUVEAUX COMPOSÉS HÉTÉROCYCLIQUES SERVANT D'ANTAGONISTES DU MGLU5
  申请人：RECORDATI IRELAND LTD

  公开号：WO2009015897A1

  公开（公告）日：2009-02-05

  In Compounds I: Z is a group of the formula, m is 0, 1 or 2; n is 0, 1 or 2; Y is a linking group or is absent; R' is H or OH or is absent; ---- is an optional double bond; and R1, R2 and R3 are selected from a wide range of optionally substituted alkyl, cycloalkyl, aryl and heterocyclic groups. Compounds I are mGlu5 antagonists useful for the treatment of neuromuscular dysfunction of the lower urinary tract, migraine and gastroesophagael reflux disease in mammals. Preferred Compounds I are those having the formula
• Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity
  作者：Andrew Anighoro、Davide Graziani、Ilaria Bettinelli、Antonio Cilia、Carlo De Toma、Matteo Longhi、Fabio Mangiarotti、Sergio Menegon、Lorenza Pirona、Elena Poggesi、Carlo Riva、Giulio Rastelli

  DOI：10.1016/j.bmc.2015.05.008

  日期：2015.7

  Metabotropic glutamate receptor 5 (mGlu(5)) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu(5). A homology model of the 7TM receptor domain built on the crystal structure of the mGlu(1) template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu(5) crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu(5) were extended to include important non-aryl alkyne mGlu(5) NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu(5) and may facilitate the design of new modulators for this class of receptors. (C) 2015 Elsevier Ltd. All rights reserved.