N-<2(S)-hydroxy-4-methylpentanoyl>-L-leucine methyl ester | 131066-51-8

• 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: N-<2(S)-hydroxy-4-methylpentanoyl>-L-leucine methyl ester
• 英文别名: methyl N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucinate；methyl (2S)-2-[[(2S)-2-hydroxy-4-methylpentanoyl]amino]-4-methylpentanoate
• CAS: 131066-51-8
• 化学式: C₁₃H₂₅NO₄
• 分子量: 259.346
• InChiKey: CZASPHZHTBQFOP-QWRGUYRKSA-N

物化性质

• 沸点：
  384.1±22.0 °C(Predicted)
• 密度：
  1.030±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-<2(S)-hydroxy-4-methylpentanoyl>-L-leucine methyl ester 在 lithium hydroxide 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 96.0h， 生成 (2S)-2-[[(2S)-2-[hydroxy-(4-methylphenyl)phosphoryl]oxy-4-methylpentanoyl]amino]-4-methylpentanoic acid
  参考文献：
  名称：

  Differential binding energy: a detailed evaluation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorus-containing inhibitors

  摘要：

  Two series of phosphorus-containing peptide analogues, 3 (Cbz-Gly-psi(PO2-CH2)Leu-Xaa) and 4 (Cbz-Gly-psi-(PO2-NH)Leu-psi[CO2]Xaa), have been synthesized and evaluated as inhibitors of the zinc endopeptidase thermolysin. In comparison with the previously reported phosphonamidates 1, the phosphinates 3 lose only 0.1 kcal/mol in binding affinity, whereas the depsipeptides 4 are bound 2.7 kcal/mol more weakly; these values are contrasted to the 4.0 kcal/mol reduction in binding affinity observed for the phosphonates 2 (Cbz-Gly-psi(PO2-O)Leu-Xaa) in comparison to 1 (Cbz-Gly-psi(PO2-NH)Leu-Xaa). The observed effects are interpreted through consideration of the differences in active-site and solvent interactions. For the comparison between the diamides 1 and the depsipeptides 4, a full accounting of the balance between these interactions can be approached. The arylphosphonates 5 (Aryl-psi(PO2-O)Leu-Leu) were synthesized and evaluated to investigate the importance of phosphonate basicity on the overall binding affinity of these zinc-coordinating inhibitors; the inhibitor K(i) values were found to be independent of phosphonate p(K)a, indicating that the basicity of the phosphonate moiety exerts counterbalancing effects on the energies of zinc coordination and solvation. For analysis of the influence of structural variations on observed affinity, the definition of "differential binding energy" is introduced as a practical alternative to the concept of "intrinsic binding energy".

  DOI：

  10.1021/ja00001a043
• 作为产物：
  描述：

  L-alpha-羟基异己酸 、 L-亮氨酸甲酯盐酸盐 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.08h， 以82%的产率得到N-<2(S)-hydroxy-4-methylpentanoyl>-L-leucine methyl ester
  参考文献：
  名称：

  [EN] NOVEL LACTAMS AND USES THEREOF
  [FR] NOUVEAUX LACTAMES ET LEURS UTILISATIONS

  摘要：

  本发明涉及具有式（I）的新化合物，其药物组合物以及它们的使用方法。这些新化合物抑制分泌酶，从而抑制淀粉样β蛋白的产生，从而防止神经沉积物的形成。本发明涉及与淀粉样β蛋白产生相关的神经系统疾病的治疗，如阿尔茨海默病。

  公开号：

  WO2004080983A1

文献信息

• [EN] NOVEL LACTAMS AND USES THEREOF<br/>[FR] NOUVEAUX LACTAMES ET LEURS UTILISATIONS
  申请人：ASTRAZENECA AB

  公开号：WO2004080983A1

  公开（公告）日：2004-09-23

  This invention relates to novel compounds having formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit secretase and thereby inhibit the production of amyloid ß protein, thereby acting to prevent the formation of neurological deposits of amyloid protein. The present invention relates to the treatment of neurological disorders related to amyloid ß - protein production such as Alzheimer's disease.

  本发明涉及具有式（I）的新化合物，其药物组合物以及它们的使用方法。这些新化合物抑制分泌酶，从而抑制淀粉样β蛋白的产生，从而防止神经沉积物的形成。本发明涉及与淀粉样β蛋白产生相关的神经系统疾病的治疗，如阿尔茨海默病。
• Novel lactams and uses thereof
  申请人：Herzog John Keith

  公开号：US20060183732A1

  公开（公告）日：2006-08-17

  This invention relates to novel compounds having formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit secretase and thereby inhibit the production of amyloid β protein, thereby acting to prevent the formation of neurological deposits of amyloid protein. The present invention relates to the treatment of neurological disorders related to amyloid β-protein production such as Alzheimer's disease.

  本发明涉及具有式（I）的新型化合物，以及它们的制药组合物和使用方法。这些新型化合物抑制分泌酶，从而抑制淀粉样β蛋白的产生，从而防止神经沉积物的淀粉样蛋白的形成。本发明涉及与淀粉样β蛋白产生相关的神经系统疾病的治疗，如阿尔茨海默病。
• Lactams and uses thereof
  申请人：AstraZeneca AB

  公开号：US07342007B2

  公开（公告）日：2008-03-11

  This invention relates to novel compounds having formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit secretase and thereby inhibit the production of amyloid β protein, thereby acting to prevent the formation of neurological deposits of amyloid protein. The present invention relates to the treatment of neurological disorders related to amyloid β-protein production such as Alzheimer's disease

  本发明涉及具有式(I)的新化合物，其制药组合物及其使用方法。这些新化合物抑制分泌酶，从而抑制淀粉样β蛋白的产生，从而防止淀粉样蛋白的神经沉积物的形成。本发明涉及与淀粉样β蛋白产生相关的神经系统疾病的治疗，如阿尔茨海默病。
• NOVEL LACTAMS AND USES THEREOF
  申请人：AstraZeneca AB

  公开号：EP1636196A1

  公开（公告）日：2006-03-22
• US7342007B2
  申请人：——

  公开号：US7342007B2

  公开（公告）日：2008-03-11