N²-[4-amino-3,5-dibromo-N-(1-oxo-4-phenylbutyl)-D-phenylalanyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine | 162178-96-3

• 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-[4-amino-3,5-dibromo-N-(1-oxo-4-phenylbutyl)-D-phenylalanyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine
• 英文别名: (2S)-2-[[(2R)-3-(4-amino-3,5-dibromophenyl)-2-(4-phenylbutanoylamino)propanoyl]amino]-6-(phenylmethoxycarbonylamino)hexanoic acid
• CAS: 162178-96-3
• 化学式: C₃₃H₃₈Br₂N₄O₆
• 分子量: 746.496
• InChiKey: JNBODMXZDCYSHD-WUFINQPMSA-N

物化性质

• 熔点：
  168-172 °C
• 沸点：
  963.0±65.0 °C(Predicted)
• 密度：
  1.456±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  45
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  160
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N²-[4-amino-3,5-dibromo-N-(1-oxo-4-phenylbutyl)-D-phenylalanyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine 在 N-甲基吗啉 、 氢溴酸 、 溶剂黄146 、 苯甲醚 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 为溶剂， 反应 0.25h， 生成 N²-[4-amino-3,5-dibromo-N-(1-oxo-4-phenylbutyl)-D-phenylalanyl]-L-lysine-phenylamide hydrobromide
  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：

  4-氨基-D-苯丙氨酸 在 N-甲基吗啉 、 potassium hydrogensulfate 、 三甲基氯硅烷 、 氢溴酸 、 溴 、 溶剂黄146 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.5h， 生成 N²-[4-amino-3,5-dibromo-N-(1-oxo-4-phenylbutyl)-D-phenylalanyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine
  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

• 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.