3-[2-chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy]-2,6-dimethylpyridine | 1362703-38-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-[2-chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy]-2,6-dimethylpyridine
• 英文别名: 3-[2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,6-dimethylpyridine
• CAS: 1362703-38-5
• 化学式: C₁₉H₂₃BClNO₃
• 分子量: 359.661
• InChiKey: DZJAVVPYLZUMES-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.44
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-溴-1-丁基-2-氧代-1,2-二氢吡啶-3-腈 、 3-[2-chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy]-2,6-dimethylpyridine 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44%的产率得到1-butyl-4-[3-chloro-4-(2,6-dimethylpyridin-3-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile
  参考文献：
  名称：

  Discovery of 1,4-Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

  摘要：

  The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

  DOI：

  10.1021/jm2016864
• 作为产物：
  描述：

  2,6-二甲基吡啶-3-醇 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 氢溴酸 、 potassium acetate 、 caesium carbonate 、 tin(ll) chloride 、 sodium nitrite 作用下， 以 乙醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 3-[2-chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy]-2,6-dimethylpyridine
  参考文献：
  名称：

  Discovery of 1,4-Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

  摘要：

  The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

  DOI：

  10.1021/jm2016864

文献信息

• 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.