1,1-dimethylethyl [[(2S,3R)-3-[(1E,3E,7E,9S)-10-(4-fluorophenoxy)-9-hydroxyl-1,3,7-decatrien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate | 524714-14-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1,1-dimethylethyl [[(2S,3R)-3-[(1E,3E,7E,9S)-10-(4-fluorophenoxy)-9-hydroxyl-1,3,7-decatrien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate
• 英文别名: tert-butyl 2-[[(2S,3R)-3-[(1E,3E,7E,9S)-10-(4-fluorophenoxy)-9-hydroxydeca-1,3,7-trien-5-ynyl]-1,4-dioxaspiro[4.5]decan-2-yl]methoxy]acetate
• CAS: 524714-14-5
• 化学式: C₃₁H₃₉FO₇
• 分子量: 542.645
• InChiKey: PORMOHHSJPORDH-VXCGDDFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  83.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl [[(2S,3R)-3-[(1E,3E,7E,9S)-10-(4-fluorophenoxy)-9-hydroxyl-1,3,7-decatrien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate 在 sodium hydroxide 、 溶剂黄146 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 21.0h， 生成 ZK-994
  参考文献：
  名称：

  Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

  摘要：

  Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

  DOI：

  10.1021/jm030569l
• 作为产物：
  描述：

  (2R,3S)-α²-(1-hydroxyethyl)-1,4-dioxaspiro[4,5]decane-2,3-dimethanol 在 sodium hydroxide 、 sodium periodate 、 copper(l) iodide 、 四(三苯基膦)钯 、 正丁基锂 、 四丁基氟化铵 、 四正丁基硫酸铵 、 二乙胺 作用下， 以 四氢呋喃 、 正己烷 、 丙酮 、 甲苯 为溶剂， 反应 24.0h， 生成 1,1-dimethylethyl [[(2S,3R)-3-[(1E,3E,7E,9S)-10-(4-fluorophenoxy)-9-hydroxyl-1,3,7-decatrien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate
  参考文献：
  名称：

  Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

  摘要：

  Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

  DOI：

  10.1021/jm030569l

文献信息

• Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo
  作者：William J. Guilford、John G. Bauman、Werner Skuballa、Shawn Bauer、Guo Ping Wei、David Davey、Caralee Schaefer、Cornell Mallari、Jennifer Terkelsen、Jih-Lie Tseng、Jun Shen、Babu Subramanyam、Arndt J. Schottelius、John F. Parkinson

  DOI：10.1021/jm030569l

  日期：2004.4.1

  Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.