3-(5-Ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-yl)-2-oxopropanoic acid | 745784-92-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: 3-(5-Ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-yl)-2-oxopropanoic acid
• CAS: 745784-92-3
• 化学式: C₁₆H₂₀O₃
• 分子量: 260.333
• InChiKey: LOSPMAPAVSVHDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(5-Ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-yl)-2-oxopropanoic acid 在 氯化亚砜 、 caesium carbonate 作用下， 以 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 26.75h， 生成 2-[(5-ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-yl)methyl]-3,3,3-trifluoro-2-hydroxy-N-(4-methyl-1-oxo-2,3-benzoxazin-6-yl)propanamide
  参考文献：
  名称：

  Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

  摘要：

  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.

  DOI：

  10.1021/jm060302x
• 作为产物：
  描述：

  5-Ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-ol 在 氢氧化钾 、 四氯化锡 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 生成 3-(5-Ethyl-6,7,8,9-tetrahydrobenzo[7]annulen-5-yl)-2-oxopropanoic acid
  参考文献：
  名称：

  Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

  摘要：

  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.

  DOI：

  10.1021/jm060302x

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：GLAXO GROUP LTD

  公开号：WO2004071389A2

  公开（公告）日：2004-08-26

  A compound of formula (I) wherein: n represents an integer 0, 1 or 2; X represents, O, S, NR6a, or CHR6b; R1 represents hydrogen, halogen such as F, Cl or Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R2 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R3 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7, CONR8R9; R4 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R5 represents H, C1-6 alkyl, or C1-6 alkenyl; R6a represents hydrogen, C1-6 alkyl, CO2C1-3 alkyl, COC1-3 alkyl or SO2C1-3 alkyl; R6b represents hydrogen, or C1-6 alkyl; R7 represents hydrogen, C1-6 alkyl, C1-3 alkyleneSiC1-3 alkyl such as -CH2CH2Si(CH3)3; R8 and R9 independently represent hydrogen or C1-6 alkyl; including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
• 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.