2-氨基-3-(5-叔丁基-3-氧代-1,2-恶唑-4-基)丙酸 | 140158-50-5

• 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
• 中文名称: 2-氨基-3-(5-叔丁基-3-氧代-1,2-恶唑-4-基)丙酸
• 英文名称: (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid
• 英文别名: 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid；(+/-)-ATPA；ATPA；(RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid；(RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid；(RS)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazolyl)propionic acid；2-Amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid；2-amino-3-(5-tert-butyl-3-oxo-1,2-oxazol-4-yl)propanoic acid
• CAS: 140158-50-5
• 化学式: C₁₀H₁₆N₂O₄
• 分子量: 228.248
• InChiKey: PIXJURSCCVBKRF-UHFFFAOYSA-N

物化性质

• 密度：
  1.263±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：10 毫克/毫升
• 稳定性/保质期：
  遵照规定使用和储存，则不会分解。

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 储存条件：
  存放于阴凉干燥处。

制备方法与用途

生物活性

ATPA 是一种选择性的谷氨酸受体 GluR5 激活剂，其 EC50 值分别为：GluR5wt、GluR5(S741M)、GluR5(S721T)、GluR5(S721T, S741M)、GluR5(S741A)、GluR5(S741L) 和 GluR5(S741V) 为 0.66 μM、9.5 μM、1.4 μM、23 μM、32 μM、18 μM 和 14 μM。

体外研究

ATPA 还激活了 GluR1wt、GluR1(M722S)、GluR1(T700S)、GluR1(T700S, M722S) 和 GluR1(M722A)，其 EC50 值分别为 62 μM、4.6 μM、97 μM、14 μM 和 97 μM。

反应信息

• 作为反应物：
  描述：

  2-氨基-3-(5-叔丁基-3-氧代-1,2-恶唑-4-基)丙酸 在 盐酸 、 三乙胺 作用下， 以 乙醇 为溶剂， 生成 ethyl (RS)-2-[N-(tert-butoxycarbonyl)amino]-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionate
  参考文献：
  名称：

  Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: Synthesis, modelling and molecular pharmacology

  摘要：

  Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (K-b = 38-161 mu M) similar to that of the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Kb = 4376 mu M). Furthermore, the AMOA analogue, la, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (Kb = 19 mu M). Unlike the iGluR antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(S)-ATPO], the corresponding tetrazolyl analogue, 1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure-activity relationships. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.06.024
• 作为产物：
  描述：

  特戊酰基乙酸乙酯 在 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 过氧化氢苯甲酰 、 盐酸羟胺 、 氢溴酸 、 sodium ethanolate 作用下， 以 四氯化碳 、 乙醚 、 乙醇 为溶剂， 反应 15.25h， 生成 2-氨基-3-(5-叔丁基-3-氧代-1,2-恶唑-4-基)丙酸
  参考文献：
  名称：

  Ibotenic Acid Analogues. Synthesis, Molecular Flexibility, and in Vitro Activity of Agonists and Antagonists at Central Glutamic Acid Receptors

  摘要：

  The syntheses of (RS)-alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid (9, ATPA), (alpha-RS, beta-RS)-alpha-amino-beta-methyl-3-hydroxy-5-isoxazolepropionic acid (8), (RS)-alpha-amino-3-hydroxy-5-isoxazolebutyric acid (15a), and (RS)-alpha-amino-3-hydroxy-5-isoxazolevaleric acid (15b) are described. The compounds were tested in vitro together with (RS)-alpha-amino-3-hydroxy-5-(bromomethyl)-4-isoxazolepropionic acid (ABPA) as inhibitors of the binding of radioactive-labeled (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to rat brain synaptic membranes. These data were compared with the earlier reported effects of the compounds on single neurons in the feline spinal cord obtained by microelectrophoretic techniques. The three compounds AMPA, ATPA, and ABPA are agonists at the class of receptors assumed to represent a subtype of physiological (S)-glutamic acid (Glu) receptors. Inhibition of [3H]AMPA binding by ATPA was 1 order of magnitude weaker than that of AMPA, in agreement with the relative potency of these compounds in vivo. ABPA proved to be equipotent with AMPA both as an inhibitor of AMPA binding and as a neuronal excitant. The compounds 8, 15a, and 15b have no effect as inhibitors of AMPA binding, in agreement with in vivo studies that have shown that 8 does not affect the firing of central neurons whereas 15a and 15b are antagonists at NMDA receptors, a subpopulation of excitatory receptors not affected by AMPA. Molecular mechanical calculations on AMPA, ATPA, and ABPA using the program MM2 showed that conformations of AMPA, ABPA, and especially ATPA by rotation of the amino acid side chain have energy barriers. A possible receptor-active conformation is suggested.

  DOI：

  10.1021/jm50001a022

文献信息

• Monomethylvaline Compounds Having Phenylalanine Side-Chain Replacements at the C-Terminus
  申请人：Doronina Svetlana O.

  公开号：US20090018086A1

  公开（公告）日：2009-01-15

  Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) are provided having C-terminal phenylalanine residue side chain replacements or modifications which are provided alone or attached to ligands through various linkers. The related conjugates can target specific cell types to provide therapeutic benefit.

  提供了MeVal-Val-Dil-Dap-Phe（MMAF）的Auristatin肽类类似物，其中包括C-末端苯丙氨酸残基侧链替换或修饰，这些类似物可以单独提供或通过各种连接剂连接到配体上。相关的结合物可以针对特定细胞类型，提供治疗效果。
• Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
  申请人：Kõster Hubert

  公开号：US20100248264A1

  公开（公告）日：2010-09-30

  Capture compounds and collections thereof and methods using the compounds for the analysis of biomolecules are provided. In particular, collections, compounds and methods are provided for analyzing complex protein mixtures, such as the proteome. The compounds are multifunctional reagents that provide for the separation and isolation of complex protein mixtures. Automated systems for performing the methods also are provided.

  提供了捕获化合物及其集合以及使用这些化合物进行生物分子分析的方法。特别地，提供了用于分析复杂蛋白质混合物（如蛋白质组）的集合、化合物和方法。这些化合物是多功能试剂，可用于分离和分离复杂的蛋白质混合物。还提供了执行这些方法的自动化系统。
• MONOMETHYLVALINE COMPOUNDS HAVING PHENYLALANINE SIDE-CHAIN MODIFICATIONS AT THE C-TERMINUS
  申请人：Seattle Genetics, Inc.

  公开号：US20130123465A1

  公开（公告）日：2013-05-16

  Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) are provided having C-terminal phenylalanine residue side chain replacements or modifications which are provided alone or attached to ligands through various linkers. The related conjugates can target specific cell types to provide therapeutic benefit.

  提供了MeVal-Val-Dil-Dap-Phe（MMAF）的Auristatin肽类类似物，其具有C-末端苯丙氨酸残基侧链替换或修饰，可单独提供或通过各种连接剂连接到配体上。相关的结合物可以定向特定的细胞类型，以提供治疗效益。
• Isatine derivatives, their preparation and use
  申请人：NEUROSEARCH A/S

  公开号：EP0432648A2

  公开（公告）日：1991-06-19

  A method of treatment with compounds having the formula wherein R¹ is hydrogen, C₁₋₆-alkyl which may be branched, C₃₋₇-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C₁₋₆-alkoxy, CH₂CO₂R' wherein R' is hydrogen or C₁₋₆-alkyl which may be branched, CH₂CN, CH₂CONRIVRV wherein RIV and RV independently are hydrogen or C₁₋₆-alkyl, or CH₂C(=NOH)NH₂; R² is hydrogen, benzyl, C₁₋₆-alkyl which may be branched, or C₃₋₇-cycloalkyl; R⁴, R⁵, R⁶, R⁷ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, SO₂NR''R''' wherein R'' and R''' independently are hydrogen or C₁₋₆-alkyl, or CF₃; or R⁶ and R⁷ together form an additional 4 to 7 membered ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR''R''' wherein R'' and R''' independently are hydrogen or C₁₋₆-alkyl, and R⁴ and R⁵ have the meanings set forth above, are disclosed, as well as pharmaceutical compositions thereof. Certain of the compounds are novel. The compounds and pharmaceutical compositions containing the compounds are useful in the treatment of central nervous system disorders and especially conditions sensitive to excitatory amino acids.

  一种用具有以下式子的化合物进行处理的方法 其中 R¹ 是氢、C₁₋₆-烷基（可以是支链）、C₃₋₇-环烷基、苄基、苯基（可以是取代的）、酰基、羟基、C₁₋₆-烷氧基、CH₂CO₂R'，其中 R' 为氢或 C₁₋₆- 烷基（可为支链）、CH₂CN、CH₂CONRIVRV，其中 RIV 和 RV 独立地为氢或 C₁₋₆- 烷基，或 CH₂C(=NOH)NH₂； R² 是氢、苄基、C₁₋₆-烷基（可以是支链）或 C₃₋₇-环烷基； R⁴、R⁵、R⁶、R⁷各自为氢、C₁₋₆-烷基（可为支链）、苯基、卤素、C₁₋₆-烷氧基、NO₂、CN、SO₂NR''R'''（其中 R'' 和 R''' 各自为氢或 C₁₋₆-烷基）或 CF₃；或 R⁶ 和 R⁷ 共同形成另外一个 4 至 7 个成员的环，该环可以是芳香族或部分饱和环，可以被卤素、NO₂、CF₃、CN、公开了 SO₂NR''R'''，其中 R'' 和 R''' 独立地为氢或 C₁₋₆ 烷基，且 R⁴ 和 R⁵ 具有上述含义，还公开了其药物组合物。其中某些化合物是新颖的。 这些化合物和含有这些化合物的药物组合物可用于治疗中枢神经系统疾病，特别是对兴奋性氨基酸敏感的疾病。
• The use of benzodiazepine compounds for preparing a pharmaceutical composition against CNS disorders related to the excitatory aminoacids
  申请人：NEUROSEARCH A/S

  公开号：EP0451626A2

  公开（公告）日：1991-10-16

  The invention relates to the use of a benzodiazepine compound having the formula wherein R³ is hydrogen, C₁₋₈-alkyl which may be branched, or cycloalkylmethyl; R⁷ and R⁸ are independently hydrogen, halogen, CF₃, CN, NO₂, NH₂, C₁₋₄-alkyl or C₁₋₄-alkoxy; and R⁴ is hydrogen and R⁵ is hydrogen or C₁₋₇-alkyl; or R⁴ and R⁵ together signify (CH₂)n wherein n is an integer of 2-3, as the active ingredient for preparing a pharmaceutical composition for treating a central nervous system disorder related to the excitatory amino acids.

  本发明涉及一种苯并二氮杂卓化合物的用途，该化合物的化学式为 其中 R³ 是氢、C₁₋₈-烷基（可以是支链）或环烷基甲基； R⁷ 和 R⁸ 独立地为氢、卤素、CF₃、CN、NO₂、NH₂、C₁₋₄-烷基或 C₁₋₄- 烷氧基；和 R⁴ 是氢，R⁵ 是氢或 C₁₋₇-烷基；或 R⁴ 和 R⁵ 共同表示 (CH₂)n，其中 n 是 2-3 的整数，作为制备治疗与兴奋性氨基酸有关的中枢神经系统疾病的药物组合物的活性成分。