2-tert-Butoxycarbonylamino-3-(4-butyl-3-methoxy-isoxazol-5-yl)-propionic acid | 204863-24-1

• 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: 2-tert-Butoxycarbonylamino-3-(4-butyl-3-methoxy-isoxazol-5-yl)-propionic acid
• 英文别名: 3-(4-Butyl-3-methoxy-1,2-oxazol-5-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 204863-24-1
• 化学式: C₁₆H₂₆N₂O₆
• 分子量: 342.392
• InChiKey: PLHCDKBEDLILFD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-tert-Butoxycarbonylamino-3-(4-butyl-3-methoxy-isoxazol-5-yl)-propionic acid 生成 (S)-(-)-2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid
  参考文献：
  名称：

  Excitatory Amino Acid Receptor Ligands:  Resolution, Absolute Stereochemistry, and Enantiopharmacology of 2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic Acid

  摘要：

  (RS)-2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (Bu-HIBO, 6) has previously been shown to be an agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors and an inhibitor of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding (J. Med. Chem. 1992, 35, 3512-3519). To elucidate the pharmacological significance of this latter binding affinity, which is also shown by quisqualic acid (3) but not by AMPA, we have now resolved Bu-HIBO via diastereomeric salt formation using the diprotected Bu-HIBO derivative 11 and the enantiomers of 1-phenylethylamine (PEA). The absolute stereochemistry of (S)-Bu-HIBO (7) (ee = 99.0%) and (R)-Bu-HIBO (8) (ee > 99.6%) were established by an X-ray crystallographic analysis of compound 15, a salt of (R)-PEA, and diprotected 8. Circular dichroism spectra of 7 and 8 were recorded. Whereas 7 (IC(50) = 0.64 mu M) and 8 (IC(50) = 0.57 mu M) were equipotent as inhibitors of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding, neither enantiomer showed significant affinity for the synaptosomal (S)-glutamic acid uptake system(s). AMPA receptor affinity (IC(50) = 0.48 mu M) and agonism (EC(50) = 17 mu M) were shown to reside exclusively in the S-enantiomer, 7. Compounds 7 and 8 did not interact detectably with kainic acid or N-methyl-D-aspartic acid (NMDA) receptor sites. Neither 7 nor 8 affected the function of the metabotropic (S)-glutamic acid receptors mGlu(2) and mGlu(4b), expressed in CHO cells. Compound 8 was shown also to be inactive at mGlu(1 alpha), whereas 7 was determined to be a moderately potent antagonist at mGlu(1 alpha) (K(i) = 110 mu M) and mGlu(5a) (K(i) = 97 mu M). Using the rat cortical wedge preparation, the AMPA receptor agonist effect of 7 was markedly potentiated by coadministration of 8 at 21 degrees C, but not at 2-4 degrees C. These observations together indicate that the potentiation of the AMPA receptor agonism of 7 by 8 is not mediated by metabotropic (S)-glutamate receptors but rather by the CaCl(2)-dependent (S)-glutamic acid binding system, which shows the characteristics of a transport mechanism. After intravenous administration in mice, 7 (ED(50) = 44 mu mol/kg) was slightly more potent than AMPA (1) (ED(50) = 55 mu mol/kg and twice as potent as Bu-HIBO (6) (ED(50) = 94 mu mol/kg) as a convulsant, whereas 8 was inactive. After subcutaneous administration in mice, Bu-HIBO (ED(50) = 110 mu mol/kg) was twice as potent as AMPA (ED(50) = 220 mu mol/kg) as a convulsant. Since 7 and Bu-HIBO (EC(50) = 37 mu M) are much weaker than AMPA (EC(50) = 3.5 mu M) as AMPA receptor agonists in vitro, the presence of a butyl group in the molecules of Bu-HIBO and 7 seems to facilitate the penetration of these compounds through the blood-brain barrier.

  DOI：

  10.1021/jm9706731
• 作为产物：
  描述：

  Dimethyl 2-acetamido-2-[(4-butyl-3-methoxy-1,2-oxazol-5-yl)methyl]propanedioate 在 盐酸 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 96.0h， 生成 2-tert-Butoxycarbonylamino-3-(4-butyl-3-methoxy-isoxazol-5-yl)-propionic acid
  参考文献：
  名称：

  Excitatory Amino Acid Receptor Ligands:  Resolution, Absolute Stereochemistry, and Enantiopharmacology of 2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic Acid

  摘要：

  (RS)-2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (Bu-HIBO, 6) has previously been shown to be an agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors and an inhibitor of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding (J. Med. Chem. 1992, 35, 3512-3519). To elucidate the pharmacological significance of this latter binding affinity, which is also shown by quisqualic acid (3) but not by AMPA, we have now resolved Bu-HIBO via diastereomeric salt formation using the diprotected Bu-HIBO derivative 11 and the enantiomers of 1-phenylethylamine (PEA). The absolute stereochemistry of (S)-Bu-HIBO (7) (ee = 99.0%) and (R)-Bu-HIBO (8) (ee > 99.6%) were established by an X-ray crystallographic analysis of compound 15, a salt of (R)-PEA, and diprotected 8. Circular dichroism spectra of 7 and 8 were recorded. Whereas 7 (IC(50) = 0.64 mu M) and 8 (IC(50) = 0.57 mu M) were equipotent as inhibitors of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding, neither enantiomer showed significant affinity for the synaptosomal (S)-glutamic acid uptake system(s). AMPA receptor affinity (IC(50) = 0.48 mu M) and agonism (EC(50) = 17 mu M) were shown to reside exclusively in the S-enantiomer, 7. Compounds 7 and 8 did not interact detectably with kainic acid or N-methyl-D-aspartic acid (NMDA) receptor sites. Neither 7 nor 8 affected the function of the metabotropic (S)-glutamic acid receptors mGlu(2) and mGlu(4b), expressed in CHO cells. Compound 8 was shown also to be inactive at mGlu(1 alpha), whereas 7 was determined to be a moderately potent antagonist at mGlu(1 alpha) (K(i) = 110 mu M) and mGlu(5a) (K(i) = 97 mu M). Using the rat cortical wedge preparation, the AMPA receptor agonist effect of 7 was markedly potentiated by coadministration of 8 at 21 degrees C, but not at 2-4 degrees C. These observations together indicate that the potentiation of the AMPA receptor agonism of 7 by 8 is not mediated by metabotropic (S)-glutamate receptors but rather by the CaCl(2)-dependent (S)-glutamic acid binding system, which shows the characteristics of a transport mechanism. After intravenous administration in mice, 7 (ED(50) = 44 mu mol/kg) was slightly more potent than AMPA (1) (ED(50) = 55 mu mol/kg and twice as potent as Bu-HIBO (6) (ED(50) = 94 mu mol/kg) as a convulsant, whereas 8 was inactive. After subcutaneous administration in mice, Bu-HIBO (ED(50) = 110 mu mol/kg) was twice as potent as AMPA (ED(50) = 220 mu mol/kg) as a convulsant. Since 7 and Bu-HIBO (EC(50) = 37 mu M) are much weaker than AMPA (EC(50) = 3.5 mu M) as AMPA receptor agonists in vitro, the presence of a butyl group in the molecules of Bu-HIBO and 7 seems to facilitate the penetration of these compounds through the blood-brain barrier.

  DOI：

  10.1021/jm9706731

文献信息

• Excitatory Amino Acid Receptor Ligands:  Resolution, Absolute Stereochemistry, and Enantiopharmacology of 2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic Acid
  作者：Tommy N. Johansen、Bjarke Ebert、Hans Bräuner-Osborne、Michael Didriksen、Inge T. Christensen、Karina K. Søby、Ulf Madsen、Povl Krogsgaard-Larsen、Lotte Brehm

  DOI：10.1021/jm9706731

  日期：1998.3.1

  (RS)-2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (Bu-HIBO, 6) has previously been shown to be an agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors and an inhibitor of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding (J. Med. Chem. 1992, 35, 3512-3519). To elucidate the pharmacological significance of this latter binding affinity, which is also shown by quisqualic acid (3) but not by AMPA, we have now resolved Bu-HIBO via diastereomeric salt formation using the diprotected Bu-HIBO derivative 11 and the enantiomers of 1-phenylethylamine (PEA). The absolute stereochemistry of (S)-Bu-HIBO (7) (ee = 99.0%) and (R)-Bu-HIBO (8) (ee > 99.6%) were established by an X-ray crystallographic analysis of compound 15, a salt of (R)-PEA, and diprotected 8. Circular dichroism spectra of 7 and 8 were recorded. Whereas 7 (IC(50) = 0.64 mu M) and 8 (IC(50) = 0.57 mu M) were equipotent as inhibitors of CaCl(2)-dependent [(3)H]-(S)-glutamic acid binding, neither enantiomer showed significant affinity for the synaptosomal (S)-glutamic acid uptake system(s). AMPA receptor affinity (IC(50) = 0.48 mu M) and agonism (EC(50) = 17 mu M) were shown to reside exclusively in the S-enantiomer, 7. Compounds 7 and 8 did not interact detectably with kainic acid or N-methyl-D-aspartic acid (NMDA) receptor sites. Neither 7 nor 8 affected the function of the metabotropic (S)-glutamic acid receptors mGlu(2) and mGlu(4b), expressed in CHO cells. Compound 8 was shown also to be inactive at mGlu(1 alpha), whereas 7 was determined to be a moderately potent antagonist at mGlu(1 alpha) (K(i) = 110 mu M) and mGlu(5a) (K(i) = 97 mu M). Using the rat cortical wedge preparation, the AMPA receptor agonist effect of 7 was markedly potentiated by coadministration of 8 at 21 degrees C, but not at 2-4 degrees C. These observations together indicate that the potentiation of the AMPA receptor agonism of 7 by 8 is not mediated by metabotropic (S)-glutamate receptors but rather by the CaCl(2)-dependent (S)-glutamic acid binding system, which shows the characteristics of a transport mechanism. After intravenous administration in mice, 7 (ED(50) = 44 mu mol/kg) was slightly more potent than AMPA (1) (ED(50) = 55 mu mol/kg and twice as potent as Bu-HIBO (6) (ED(50) = 94 mu mol/kg) as a convulsant, whereas 8 was inactive. After subcutaneous administration in mice, Bu-HIBO (ED(50) = 110 mu mol/kg) was twice as potent as AMPA (ED(50) = 220 mu mol/kg) as a convulsant. Since 7 and Bu-HIBO (EC(50) = 37 mu M) are much weaker than AMPA (EC(50) = 3.5 mu M) as AMPA receptor agonists in vitro, the presence of a butyl group in the molecules of Bu-HIBO and 7 seems to facilitate the penetration of these compounds through the blood-brain barrier.