4-{4-[(S)-3-(3-Carbamimidoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carbonyl}-piperidine-1-carboxamidine

• 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: 4-{4-[(S)-3-(3-Carbamimidoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carbonyl}-piperidine-1-carboxamidine
• 英文别名: (S)-4-(4-(3-(3-Carbamimidoylphenyl)-2-(2,4,6-triisopropylphenylsulfonamido)propanoyl)piperazine-1-carbonyl)piperidine-1-carboximidamide；4-[4-[(2S)-3-(3-carbamimidoylphenyl)-2-[[2,4,6-tri(propan-2-yl)phenyl]sulfonylamino]propanoyl]piperazine-1-carbonyl]piperidine-1-carboximidamide
• 化学式: C₃₆H₅₄N₈O₄S
• 分子量: 694.942
• InChiKey: KSEVHDWJTMMENT-HKBQPEDESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  49
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  198
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  在 palladium on activated charcoal 盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-{4-[(S)-3-(3-Carbamimidoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carbonyl}-piperidine-1-carboxamidine
  参考文献：
  名称：

  Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective Inhibitors of Matriptase

  摘要：

  Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.

  DOI：

  10.1021/jm051272l

文献信息

• MACROCYCLIC INHIBITORS OF SERINE PROTEASE ENZYMES
  申请人：Marsault Éric

  公开号：US20120270807A1

  公开（公告）日：2012-10-25

  The present invention relates to novel macrocyclic compounds and salts thereof that bind to and/or are inhibitors of serine protease enzymes. The present invention also relates to intermediates of these compounds, pharmaceutical compositions containing these compounds and methods of using the compounds. These compounds are useful as therapeutics for treatment and prevention of a range of disease indications including hyperproliferative disorders, in particular those characterized by tumor metastasis, inflammatory disorders, skin and tissue disorders, cardiovascular disorders, respiratory disorders and viral infections.

  本发明涉及新型大环化合物及其盐，它们能结合和/或抑制丝氨酸蛋白酶酶。本发明还涉及这些化合物的中间体，含有这些化合物的制药组合物以及使用这些化合物的方法。这些化合物可用于治疗和预防一系列疾病指标，包括增生性疾病，特别是那些以肿瘤转移为特征的疾病，炎症性疾病，皮肤和组织疾病，心血管疾病，呼吸系统疾病和病毒感染。
• METHODS OF USING MACROCYCLIC INHIBITORS OF SERINE PROTEASE ENZYMES
  申请人：Marsault Éric

  公开号：US20120270769A1

  公开（公告）日：2012-10-25

  The present invention relates to novel macrocyclic compounds and salts thereof that bind to and/or are inhibitors of serine protease enzymes and methods of using the compounds. The present invention also relates to intermediates of these compounds, pharmaceutical compositions containing these compounds and methods of using the same. These compounds are useful as therapeutics for treatment and prevention of a range of disease indications including hyperproliferative disorders, in particular those characterized by tumor metastasis, inflammatory disorders, skin and tissue disorders, cardiovascular disorders, respiratory disorders and viral infections.

  本发明涉及新型大环化合物及其盐，这些化合物与/或抑制丝氨酸蛋白酶酶的结合，并使用这些化合物的方法。本发明还涉及这些化合物的中间体、含有这些化合物的制药组合物以及使用它们的方法。这些化合物可用作治疗和预防一系列疾病指标的治疗剂，包括高增殖性疾病，特别是肿瘤转移、炎症性疾病、皮肤和组织疾病、心血管疾病、呼吸系统疾病和病毒感染。
• Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective Inhibitors of Matriptase
  作者：Torsten Steinmetzer、Andrea Schweinitz、Anne Stürzebecher、Daniel Dönnecke、Kerstin Uhland、Oliver Schuster、Peter Steinmetzer、Friedemann Müller、Rainer Friedrich、Manuel E. Than、Wolfram Bode、Jörg Stürzebecher

  DOI：10.1021/jm051272l

  日期：2006.7.1

  Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.