N²-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide | 864738-87-4

• 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-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide
• 英文别名: Boc-D-Tyr(3,5-diBr)-Lys(Cbz)-NHEtPh；benzyl N-[(5S)-5-[[(2R)-3-(3,5-dibromo-4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-6-oxo-6-(2-phenylethylamino)hexyl]carbamate
• CAS: 864738-87-4
• 化学式: C₃₆H₄₄Br₂N₄O₇
• 分子量: 804.576
• InChiKey: PBLNJLDVWMYABO-XZWHSSHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  49
• 可旋转键数：
  19
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  155
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N²-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N⁶-(phenylmethoxycarbonyl)-L-lysine-2-phenethylamide 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以58%的产率得到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：

  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 2.25h， 生成 N²-[N-(1,1-dimethylethoxycarbonyl)-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