ethyl 2-acetamido-2-ethoxycarbonyl-3-(3-ethoxy-4-phenyl-5-isoxazolyl)propionate | 334887-46-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 2-acetamido-2-ethoxycarbonyl-3-(3-ethoxy-4-phenyl-5-isoxazolyl)propionate
• 英文别名: Diethyl 2-acetamido-2-[(3-ethoxy-4-phenyl-1,2-oxazol-5-yl)methyl]propanedioate
• CAS: 334887-46-6
• 化学式: C₂₁H₂₆N₂O₇
• 分子量: 418.447
• InChiKey: SDRFPIKNGWNFQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  30
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  117
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 2-acetamido-2-ethoxycarbonyl-3-(3-ethoxy-4-phenyl-5-isoxazolyl)propionate 在 48percent aq. HBr 作用下， 反应 0.5h， 以85%的产率得到2-Amino-3-(3-hydroxy-4-phenyl-isoxazol-5-yl)-propionic acid
  参考文献：
  名称：

  Synthesis and Pharmacology of 3-Isoxazolol Amino Acids as Selective Antagonists at Group I Metabotropic Glutamic Acid Receptors

  摘要：

  Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antagonist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 muM, respectively). Compound 9, administered icy, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.

  DOI：

  10.1021/jm000441t
• 作为产物：
  描述：

  3-hydroxy-5-methyl-4-phenylisoxazole 在 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 、 potassium carbonate 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 43.75h， 生成 ethyl 2-acetamido-2-ethoxycarbonyl-3-(3-ethoxy-4-phenyl-5-isoxazolyl)propionate
  参考文献：
  名称：

  Synthesis and Pharmacology of 3-Isoxazolol Amino Acids as Selective Antagonists at Group I Metabotropic Glutamic Acid Receptors

  摘要：

  Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antagonist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 muM, respectively). Compound 9, administered icy, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.

  DOI：

  10.1021/jm000441t

文献信息

• Synthesis and Pharmacology of 3-Isoxazolol Amino Acids as Selective Antagonists at Group I Metabotropic Glutamic Acid Receptors
  作者：Ulf Madsen、Hans Bräuner-Osborne、Karla Frydenvang、Lise Hvene、Tommy N. Johansen、Birgitte Nielsen、Connie Sánchez、Tine B. Stensbøl、Francois Bischoff、Povl Krogsgaard-Larsen

  DOI：10.1021/jm000441t

  日期：2001.3.1

  Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antagonist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 muM, respectively). Compound 9, administered icy, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.