(4R,5S)-5-[(tert-Butoxycarbonyl)amino]-4-hydroxy-7-methyloct-2-ynoate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羟基酸及其衍生物
• 英文名称: (4R,5S)-5-[(tert-Butoxycarbonyl)amino]-4-hydroxy-7-methyloct-2-ynoate
• 英文别名: ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyloct-2-ynoate；(4R,5S)-4-hydroxy-7-methyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]oct-2-ynoic acid
• 化学式: C₁₄H₂₃NO₅
• 分子量: 285.34
• InChiKey: ABGGWFXZHLESHY-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  95.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-甲基-2-丙基[(2S)-4-甲基-1-氧代-2-戊烷基]氨基甲酸酯 、 丙炔酸乙酯 在 正丁基锂 、 二异丙胺 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 以42%的产率得到(4R,5S)-5-[(tert-Butoxycarbonyl)amino]-4-hydroxy-7-methyloct-2-ynoate
  参考文献：
  名称：

  Inhibitors of memapsin 2 and use thereof

  摘要：

  已开发出生产纯化、具有催化活性的重组memapsin 2的方法。通过一种方法确定了具有催化活性的酶的底物和亚位点特异性，该方法利用MALDI-TOF/MS测定了底物的初始水解速率。另外，memapsin的亚位点特异性可以通过使用memapsin 2探测抑制剂库，并随后使用对memapsin 2产生的抗体和碱性磷酸酶结合的二抗检测已结合的memapsin 2来确定。底物和亚位点特异性信息被用来设计模拟天然memapsin 2底物的底物类似物，可以抑制memapsin 2的功能。这些底物类似物基于肽序列，已证明与memapsin 2的天然肽底物相关。底物类似物包含至少一个酰胺键的类似物，该键无法被memapsin 2水解。开发了包括在关键氨基酸残基位点处的同位素的底物类似物合成过程，合成了七十多种底物类似物，其中MMI-005、MMI-012、MMI-017、MMI-018、MMI-025、MMI-026、MMI-037、MMI-039、MMI-040、MMI-066、MMI-070和MMI-071对重组前memapsin 2的抑制常数在1.4-61.4×10^-9M范围内。这些抑制剂在诊断和治疗和/或预防阿尔茨海默病中非常有用。

  公开号：

  US20030092629A1

文献信息

• [EN] BICYCLIC COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF<br/>[FR] COMPOSES BICYCLIQUES INHIBANT L'ACTIVITE DE LA BETA-SECRETASE ET PROCEDES D'UTILISATION ASSOCIES
  申请人：ZAPAQ INC

  公开号：WO2006034277A1

  公开（公告）日：2006-03-30

  The present invention provides bicyclic beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer’s disease.

  本发明提供了双环β-分泌酶抑制剂及其用途，包括用于治疗阿尔茨海默病的方法。
• Amino-Containing Compounds Which Inhibit Memapsin 2 Beta-Secretase Activity and Methods of Use Thereof
  申请人：Ghosh Arun K.

  公开号：US20080125467A1

  公开（公告）日：2008-05-29

  The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.

  本发明提供了新型β-分泌酶抑制剂及其使用方法，包括治疗阿尔茨海默病的方法。
• Compounds which inhibit beta-secretase activity and methods of use thereof
  申请人：Oklahoma Medical Research Foundation

  公开号：US20040121947A1

  公开（公告）日：2004-06-24

  Compounds inhibit memapsin 2 &bgr;-secretase activity and selectively inhibit memapsin 2 &bgr;-secretase activity relative to memapsin 1 &bgr;-secretase activity. The compounds are employed in methods to inhibit memapsin 2 &bgr;-secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a &bgr;-secretase site of a &bgr;amyloid precursor protein and to decrease &bgr;-amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.

  这些化合物抑制memapsin 2 β-分泌酶活性，并相对选择性地抑制memapsin 2 β-分泌酶活性，而相对于memapsin 1 β-分泌酶活性。这些化合物用于抑制memapsin 2 β-分泌酶活性的方法，用于治疗阿尔茨海默病，用于抑制β淀粉样前体蛋白的β-分泌酶位点的水解，并用于减少体外样本和哺乳动物中的β-淀粉样蛋白。与本发明的化合物相关的memapsin 2蛋白被结晶。
• Inhibitors of Memapsin 2 and use thereof
  申请人：Oklahoma Medical Research Foundation

  公开号：US20040220079A1

  公开（公告）日：2004-11-04

  Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. 1 ). The inhibition constant of OM99-2 is 1.6×10 −9 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

  已开发出生产纯化的催化活性重组膜酶2的方法。已确定催化活性酶的底物和亚位点特异性。利用底物和亚位点特异性信息设计了天然膜酶2底物的底物类似物，可以抑制膜酶2的功能。底物类似物基于肽序列，显示与膜酶2的天然肽底物相关。底物类似物至少包含一种酰胺键的类似物，该键无法被膜酶2裂解。开发了两种底物类似物的合成过程，包括在关键氨基酸残基的位置上的等构体，并合成了底物类似物OMR99-1和OM99-2。OM99-2基于一个八肽Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe（SEQ ID NO:28），其中Leu-Ala肽键被过渡态等构体羟基乙烯基（FIG.1）所取代。OM99-2的抑制常数为1.6×10−9M，针对重组前膜酶2。膜酶2结合该抑制剂的晶体学被用于确定蛋白质的三维结构，以及各种残基在结合中的重要性。这些信息可以被熟练掌握有机化学和酶学技术的人用于设计新的抑制剂，利用商业软件程序和技术，用于诊断和治疗和/或预防阿尔茨海默病。
• Catalytically active recombinant memapsin and methods of use thereof
  申请人：Oklahoma Medical Research Foundation

  公开号：US20020164760A1

  公开（公告）日：2002-11-07

  Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. 1 ). The inhibition constant of OM99-2 is 1.6×10 −9 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

  已经开发出了生产纯化的、催化活性的重组memapsin 2的方法。已经确定了催化活性酶的底物和底物位点特异性。底物和底物位点特异性信息被用来设计模拟天然memapsin 2底物的底物类似物，以抑制memapsin 2的功能。底物类似物基于肽序列，已经显示与memapsin 2的天然肽底物相关。底物类似物包含至少一个酰胺键的类似物，该键不能被memapsin 2裂解。开发了两种底物类似物的合成过程，包括在关键氨基酸残基位点上的同分异构体，合成了底物类似物OMR99-1和OM99-2。OM99-2基于一个八肽Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe（SEQ ID NO:28），其中Leu-Ala肽键被过渡态类似物羟基乙烯基（FIG.1）替代。OM99-2对重组前memapsin 2的抑制常数为1.6×10-9M。memapsin 2与该抑制剂结合的晶体学被用于确定蛋白质的三维结构，以及各种残基在结合中的重要性。这些信息可以被熟练掌握有机化学和酶学技术的人们使用商业软件程序和技术来设计新的memapsin 2抑制剂，用于诊断和治疗和/或预防阿尔茨海默病。