ethyl (E,E)-(S,S)-3-{4-[3-(4'-{4-(4-(2-ethoxy-2-ethoxycarbonylethyl)phenoxy)but-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate | 516517-66-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl (E,E)-(S,S)-3-{4-[3-(4'-{4-(4-(2-ethoxy-2-ethoxycarbonylethyl)phenoxy)but-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate
• 英文别名: (E)(E)(S)(S) 2-Ethoxy-3-{4-[3-(4'-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester；ethyl (2S)-3-[4-[(E)-3-[4-[4-[(E)-4-[4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy]but-2-en-2-yl]phenyl]phenyl]but-2-enoxy]phenyl]-2-ethoxypropanoate
• CAS: 516517-66-1
• 化学式: C₄₆H₅₄O₈
• 分子量: 734.93
• InChiKey: WHFFYNUOTNZEBZ-ZKCGRHEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.6
• 重原子数：
  54
• 可旋转键数：
  23
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  89.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl (E,E)-(S,S)-3-{4-[3-(4'-{4-(4-(2-ethoxy-2-ethoxycarbonylethyl)phenoxy)but-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 19.0h， 以53%的产率得到(S)-3-{4-[(E)-3-(4'-{(E)-3-[4-((S)-2-Carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid
  参考文献：
  名称：

  Large Dimeric Ligands with Favorable Pharmacokinetic Properties and Peroxisome Proliferator-Activated Receptor Agonist Activity in Vitro and in Vivo

  摘要：

  Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

  DOI：

  10.1021/jm0309046
• 作为产物：
  描述：

  ethyl (E)-3-(4-iodophenyl)but-2-enoate 在 咪唑 、 四(三苯基膦)钯 、 三丁基膦 、 四丁基氟化铵 、 sodium ethanolate 、 二异丁基氢化铝 、 sodium carbonate 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 65.58h， 生成 ethyl (E,E)-(S,S)-3-{4-[3-(4'-{4-(4-(2-ethoxy-2-ethoxycarbonylethyl)phenoxy)but-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate
  参考文献：
  名称：

  Large Dimeric Ligands with Favorable Pharmacokinetic Properties and Peroxisome Proliferator-Activated Receptor Agonist Activity in Vitro and in Vivo

  摘要：

  Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

  DOI：

  10.1021/jm0309046
• 作为试剂：
  描述：

  (E)(S) 3-{4-[3-(4'-{3-[(tert-butyidimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester 、 、 四丁基氟化铵 在 ethyl (E,E)-(S,S)-3-{4-[3-(4'-{4-(4-(2-ethoxy-2-ethoxycarbonylethyl)phenoxy)but-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate 、 ice 、 乙酸乙酯 、 Brine 、 magnesium sulfate 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 为溶剂， 反应 3.0h， 以to give 0.94 g of (E)(E)(S) 2-ethoxy-3-(4-{3-[4′-{3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic acid ethyl ester的产率得到ethyl (E,E)-(S)-3-{4-[3-(4'-{4-hydroxybut-2-en-2-yl}biphenyl-4-yl)but-2-en-1-yloxy]phenyl}-2-ethoxypropanoate
  参考文献：
  名称：

  Novel compounds, their preparation and use

  摘要：

  一种新型的二羧酸衍生物类，这些化合物的用途是制成药物组合物，包括这些化合物的药物组合物以及使用这些化合物和组合物的治疗方法。这些化合物可能在治疗和/或预防由过氧化物酶体增殖物激活受体（PPAR）介导的疾病方面有用。

  公开号：

  US20030109579A1

文献信息

• Compounds, their preparation and use
  申请人：Novo Nordisk A/S

  公开号：US07220877B2

  公开（公告）日：2007-05-22

  A novel class of dicarboxylic acid derivatives, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).

  一种新型的二羧酸衍生物，这些化合物作为药物组成物的使用，包括这些化合物的药物组成物和使用这些化合物和组成物的治疗方法。这些化合物可能有助于治疗和/或预防由过氧化物酶体增殖物激活受体（PPAR）介导的疾病。
• Large Dimeric Ligands with Favorable Pharmacokinetic Properties and Peroxisome Proliferator-Activated Receptor Agonist Activity in Vitro and in Vivo
  作者：Per Sauerberg、Paul S. Bury、John P. Mogensen、Heinz-Josef Deussen、Ingrid Pettersson、Jan Fleckner、Jan Nehlin、Klaus S. Frederiksen、Tatjana Albrektsen、Nanni Din、L. Anders Svensson、Lars Ynddal、Erik M. Wulff、Lone Jeppesen

  DOI：10.1021/jm0309046

  日期：2003.11.1

  Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.
• Novel compounds, their preparation and use
  申请人：——

  公开号：US20030109579A1

  公开（公告）日：2003-06-12

  A novel class of dicarboxylic acid derivatives, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).

  一种新型的二羧酸衍生物类，这些化合物的用途是制成药物组合物，包括这些化合物的药物组合物以及使用这些化合物和组合物的治疗方法。这些化合物可能在治疗和/或预防由过氧化物酶体增殖物激活受体（PPAR）介导的疾病方面有用。