6-benzyl-2-((3-fluorophenoxy)methyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one | 1616293-33-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-benzyl-2-((3-fluorophenoxy)methyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one
• 英文别名: 6-Benzyl-2-[(3-fluorophenoxy)methyl]-7,8-dihydro-1,6-naphthyridin-5-one；6-benzyl-2-[(3-fluorophenoxy)methyl]-7,8-dihydro-1,6-naphthyridin-5-one
• CAS: 1616293-33-4
• 化学式: C₂₂H₁₉FN₂O₂
• 分子量: 362.403
• InChiKey: LNWRCPWIKGWYIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氯-7,8-二氢-1,6-萘啶-5(6h)-酮 在 sodium tetrahydroborate 、 四(三苯基膦)钯 、 ammonium cerium (IV) nitrate 、 偶氮二甲酸二异丙酯 、 potassium tert-butylate 、 caesium carbonate 、 臭氧 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 66.25h， 生成 6-benzyl-2-((3-fluorophenoxy)methyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one
  参考文献：
  名称：

  Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

  摘要：

  Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu(5) PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu(5) as well as antagonist activity at mGlu(3). Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu(5) PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

  DOI：

  10.1021/jm500259z

文献信息

• Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)
  作者：Mark Turlington、Chrysa Malosh、Jon Jacobs、Jason T. Manka、Meredith J. Noetzel、Paige N. Vinson、Satyawan Jadhav、Elizabeth J. Herman、Hilde Lavreysen、Claire Mackie、José M. Bartolomé-Nebreda、Susana Conde-Ceide、M. Luz Martín-Martín、Han Min Tong、Silvia López、Gregor J. MacDonald、Thomas Steckler、J. Scott Daniels、C. David Weaver、Colleen M. Niswender、Carrie K. Jones、P. Jeffrey Conn、Craig W. Lindsley、Shaun R. Stauffer

  DOI：10.1021/jm500259z

  日期：2014.7.10

  Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu(5) PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu(5) as well as antagonist activity at mGlu(3). Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu(5) PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.