N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide | 745784-53-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide
• 英文别名: N-(4-methyl-1-oxo-2,3-benzoxazin-6-yl)-2-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide
• CAS: 745784-53-6
• 化学式: C₂₂H₂₀N₂O₄
• 分子量: 376.412
• InChiKey: PYYYTCRTPMLXMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  84.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide 、 (三氟甲基)三甲基硅烷 在 caesium carbonate 、 四丁基氟化铵 作用下， 以 N,N-二甲基甲酰胺 、 四氢呋喃 为溶剂， 反应 0.5h， 生成 3,3,3-trifluoro-2-hydroxy-N-(4-methyl-1-oxo-2,3-benzoxazin-6-yl)-2-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)propanamide
  参考文献：
  名称：

  Design and Synthesis of New Nonsteroidal Glucocorticoid Modulators through Application of an “Agreement Docking” Method

  摘要：

  Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.

  DOI：

  10.1021/jm050345y
• 作为产物：
  描述：

  ethyl (2E/2Z)-2-ethoxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enoate 在 氯化亚砜 、 三氟乙酸 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 6.0h， 生成 N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide
  参考文献：
  名称：

  Design and Synthesis of New Nonsteroidal Glucocorticoid Modulators through Application of an “Agreement Docking” Method

  摘要：

  Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.

  DOI：

  10.1021/jm050345y

文献信息

• Design and Synthesis of New Nonsteroidal Glucocorticoid Modulators through Application of an “Agreement Docking” Method
  作者：Mike Barker、Margaret Clackers、Derek A. Demaine、Davina Humphreys、Michael J. Johnston、Haydn T. Jones、Francois Pacquet、John M. Pritchard、Mark Salter、Stephen E. Shanahan、Philip A. Skone、Victoria M. Vinader、Iain Uings、Iain M. McLay、Simon J. F. Macdonald

  DOI：10.1021/jm050345y

  日期：2005.7.1

  Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.
• Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series
  作者：Mike Barker、Margaret Clackers、Royston Copley、Derek A. Demaine、Davina Humphreys、Graham G. A. Inglis、Michael J. Johnston、Haydn T. Jones、Michael V. Haase、David House、Richard Loiseau、Lesley Nisbet、Francois Pacquet、Philip A. Skone、Stephen E. Shanahan、Dan Tape、Victoria M. Vinader、Melanie Washington、Iain Uings、Richard Upton、Iain M. McLay、Simon J. F. Macdonald

  DOI：10.1021/jm060302x

  日期：2006.7.1

  The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.