N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide | 145730-89-8

• 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: N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide
• 英文别名: Boc-Lys(Z)-PEA；Boc-Lys(Cbz)-NHEtPh；benzyl N-[(5S)-5-[(2-methylpropan-2-yl)oxycarbonylamino]-6-oxo-6-(2-phenylethylamino)hexyl]carbamate
• CAS: 145730-89-8
• 化学式: C₂₇H₃₇N₃O₅
• 分子量: 483.608
• InChiKey: IOJDLEHMUGKKKN-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  35
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide 在 N-甲基吗啉 、 三氟乙酸 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.25h， 生成 N2-[3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide
  参考文献：
  名称：

  Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine

  摘要：

  Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.

  DOI：

  10.1021/jm0490641
• 作为产物：
  描述：

  N-Boc-N'-Cbz-L-赖氨酸 、 2-苯乙胺 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以92%的产率得到N²-(1,1-dimethylethoxycarbonyl)-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide
  参考文献：
  名称：

  Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine

  摘要：

  Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.

  DOI：

  10.1021/jm0490641

文献信息

• Conformationally Constrained [<i>p</i>-(ω-Aminoalkyl)phenacetyl]-<scp>l</scp>-seryl-<scp>l</scp>-lysyl Dipeptide Amides as Potent Peptidomimetic Inhibitors of <i>Candida albicans</i> and Human Myristoyl-CoA:Protein <i>N</i>-Myristoyl Transferase
  作者：Srinivasan R. Nagarajan、Balekudru Devadas、Mark E. Zupec、Sandra K. Freeman、David L. Brown、Hwang-Fun Lu、Pramod P. Mehta、Nandini S. Kishore、Charles A. McWherter、Daniel P. Getman、Jeffrey I. Gordon、James A. Sikorski

  DOI：10.1021/jm9608671

  日期：1997.5.1

  inhibitor containing an N-(cyclohexylethyl)lysinamide (17e, IC50 = 0.11 +/- 0.03 microM). Partial rigidification of the flexible aminoundecanoyl chain produced the dipeptide p-(omega-aminohexyl)phenacetyl-L-seryl-L-lysyl-N-(cyclohexyleth yl)amide (26b, IC50 = 0.11 +/- 0.04 microM). Subsequent incorporation of an alpha-methyl substituent into 26b provided the dipeptide analog [2-[p-(omega-aminohexyl)ph

  肉豆蔻酰基CoA：蛋白N-肉豆蔻酰基转移酶（NMT）通过酰胺键将14个碳的饱和肉豆蔻酸脂肪酸酯共价连接到多种细胞蛋白的N末端甘氨酸残基上。遗传研究表明，NMT对于主要真菌病原体的生存至关重要，这些病原体会在免疫抑制的人类中引起系统性感染，因此是开发杀菌药物的目标。我们已经从一种这样的真菌病原体白色念珠菌中产生了一类有效的NMT拟肽抑制剂。将底物类似物抑制剂ALYASKL-NH2的N末端四肽替换为具有最佳11-碳链抑制作用的ω-氨基链烷酰基部分（11-氨基十一烷酰基-SKL-NH2，3a，IC50 = 1.2 +/- 0.14 microM）。C末端Leu的一系列替代物确定含有亲脂性侧链的残基最有效，其中环己基丙氨酸的效价最大（3g，IC50 = 0.36 +/- 0.06 microM）。羧酰胺部分的除去导致含有N-（环己基乙基）赖氨酰胺的代谢稳定的二肽抑制剂（17e，IC 50 ＝ 0.11
• Boomgaarden; Heinrich; Henklein, Pharmazie, 1992, vol. 47, # 9, p. 710 - 711
  作者：Boomgaarden、Heinrich、Henklein

  DOI：——

  日期：——
• Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[<i>N</i>²-[3,5-Dibromo-<i>N</i>-[[4-(3,4-dihydro-2(1<i>H</i>)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-<scp>d</scp>-tyrosyl]-<scp>l</scp>-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine
  作者：Klaus Rudolf、Wolfgang Eberlein、Wolfhard Engel、Helmut Pieper、Michael Entzeroth、Gerhard Hallermayer、Henri Doods

  DOI：10.1021/jm0490641

  日期：2005.9.1

  Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.