2-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine | 1255311-67-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine
• 英文别名: 2-Cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine
• CAS: 1255311-67-1
• 化学式: C₂₀H₂₃BFNO₃
• 分子量: 355.217
• InChiKey: FDTJWMBISJFHIN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.19
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-氯-3-(环丙基甲基)-7-碘-[1,2,4]三唑并[4,3-A]吡啶 、 2-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine 在 四(三苯基膦)钯 、 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.17h， 以45%的产率得到8-chloro-3-cyclopropylmethyl-7-{4-[(2-cyclopropylpyridin-4-yl)oxy]-3-fluorophenyl}[1,2,4]triazolo[4,3-a]pyridine
  参考文献：
  名称：

  Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

  摘要：

  We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-c]pyridines with mGlu(2) positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k(on), k(off) and residence time (RT) were determined. The PAMs showed various kinetic profiles; k(on) values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k(on) was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu(2) PAMs with high values for k(on) but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.

  DOI：

  10.1021/acs.jmedchem.7b00669
• 作为产物：
  描述：

  4-(4-bromo-2-fluoro-phenoxy)-2-cyclopropyl-pyridine 、 联硼酸频那醇酯 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 potassium acetate 作用下， 以 1,4-二氧六环 为溶剂， 以79%的产率得到2-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine
  参考文献：
  名称：

  [EN] 7-ARYL-1,2,4-TRIAZOLO[4,3-A]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
  [FR] DÉRIVÉS DE LA 7-ARYL-1,2,4-TRIAZOLO [4,3-A] PYRIDINE ET LEUR UTILISATION EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DES RÉCEPTEURS MGLUR2

  摘要：

  本发明涉及新型Formula (I)的三唑并[4,3-a]吡啶衍生物，其中所有基团如权利要求中所定义。根据本发明的化合物是代谢型谷氨酸受体亚型2 ("mGluR2")的阳性变构调节剂，适用于治疗或预防与谷氨酸功能障碍有关的神经和精神疾病，以及mGluR2代谢型受体亚型参与的疾病。本发明还涉及包括这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及利用这些化合物预防或治疗与mGluR2有关的神经和精神疾病和疾病的用途。

  公开号：

  WO2010130423A1

文献信息

• [EN] 7-ARYL-1,2,4-TRIAZOLO[4,3-A]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS<br/>[FR] DÉRIVÉS DE LA 7-ARYL-1,2,4-TRIAZOLO [4,3-A] PYRIDINE ET LEUR UTILISATION EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DES RÉCEPTEURS MGLUR2
  申请人：ORTHO MCNEIL JANSSEN PHARM

  公开号：WO2010130423A1

  公开（公告）日：2010-11-18

  The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 ("mGluR2"), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

  本发明涉及新型Formula (I)的三唑并[4,3-a]吡啶衍生物，其中所有基团如权利要求中所定义。根据本发明的化合物是代谢型谷氨酸受体亚型2 ("mGluR2")的阳性变构调节剂，适用于治疗或预防与谷氨酸功能障碍有关的神经和精神疾病，以及mGluR2代谢型受体亚型参与的疾病。本发明还涉及包括这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及利用这些化合物预防或治疗与mGluR2有关的神经和精神疾病和疾病的用途。
• Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-<i>a</i>]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2
  作者：Maarten L. J. Doornbos、José María Cid、Jordi Haubrich、Alexandro Nunes、Jasper W. van de Sande、Sophie C. Vermond、Thea Mulder-Krieger、Andrés A. Trabanco、Abdellah Ahnaou、Wilhelmus H. Drinkenburg、Hilde Lavreysen、Laura H. Heitman、Adriaan P. IJzerman、Gary Tresadern

  DOI：10.1021/acs.jmedchem.7b00669

  日期：2017.8.10

  We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-c]pyridines with mGlu(2) positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k(on), k(off) and residence time (RT) were determined. The PAMs showed various kinetic profiles; k(on) values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k(on) was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu(2) PAMs with high values for k(on) but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.