(R)-5-(2-chlorophenyl)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-5-(2-chlorophenyl)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
• 英文别名: (7R)-5-(2-chlorophenyl)-2-[(5-fluoropyridin-2-yl)oxymethyl]-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one
• 化学式: C₁₉H₁₆ClFN₄O₂
• 分子量: 386.813
• InChiKey: HYAAZJQYLLTXKU-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  60.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  ethyl 2,4-dioxo-5-phenoxypentanoate 在 盐酸 、 copper(l) iodide 、 三溴化硼 、 sodium hydride 、 碳酸氢钠 、 potassium carbonate 、 一水合肼 、 三苯基膦 、 lithium hydroxide 、 N,N'-二甲基乙二胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 21.16h， 生成 (R)-5-(2-chlorophenyl)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
  参考文献：
  名称：

  Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

  摘要：

  Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu(2) and mGlu(3)) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu(3) NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu(5) positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu(3) NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

  DOI：

  10.1021/acs.jmedchem.5b01005

文献信息

• Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
  作者：Julie L. Engers、Alice L. Rodriguez、Leah C. Konkol、Ryan D. Morrison、Analisa D. Thompson、Frank W. Byers、Anna L. Blobaum、Sichen Chang、Daryl F. Venable、Matthew T. Loch、Colleen M. Niswender、J. Scott Daniels、Carrie K. Jones、P. Jeffrey Conn、Craig W. Lindsley、Kyle A. Emmitte

  DOI：10.1021/acs.jmedchem.5b01005

  日期：2015.9.24

  Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu(2) and mGlu(3)) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu(3) NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu(5) positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu(3) NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.