repertaxin | 266359-83-5

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: repertaxin
• 英文别名: (2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide；R(-)-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide；R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide；R-(-)-2-(4-isobutylphenyl)propionyl methansulphonamide；reparixin
• CAS: 266359-83-5
• 化学式: C₁₄H₂₁NO₃S
• 分子量: 283.392
• InChiKey: KQDRVXQXKZXMHP-LLVKDONJSA-N

物化性质

• 熔点：
  103-105℃
• 密度：
  1.137±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于 DMSO（高达 100 mg/ml）或乙醇（高达 25 mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20℃

制备方法与用途

生物活性

Reparixin (Repertaxin, DF 1681Y) 是一种有效且特异性的 CXCR1 抑制剂，IC50 值为 1 nM。它能够抑制 CXCL8 诱导的中性粒细胞迁移（IC50 = 1 nM），以及 CXCL1 和 CXCL2 引起的小鼠中性粒细胞趋化性。此外，Reparixin 还可与 CXCR2 结合，并且能够抑制人中性粒细胞对 CXCL1 的反应（IC50 = 400 nM）。

靶点	值
CXCR1 (离体试验)	1 nM
CXCL8 (离体试验)	1 nM
CXCR2 (离体试验)	400 nM

体外研究

Reparixin 是一种非竞争性 CXCR1 和 CXCR2 激活的变构抑制剂，它能有效抑制胞内信号通路而不会影响受体结合。Reparixin 可以选择性地抑制 CXCL8 诱导的各种生物过程，包括白细胞募集和功能性炎症反应。此外，Reparixin 不会影响其他趋化因子 C5a、fMLP 和 CXCL12 对 CXCR1/CXCR2 的激活。体外研究还表明，Reparixin 可以调控血管紧张素 II 受体的产生，并影响 Ang II 引起的高血压。它能够特异性地阻止 CXCR1/2 介导的小鼠和人中性粒细胞迁移，而不干扰其他受体的功能。此外，Reparixin 还可以抑制 CXCL8 诱导的中性粒细胞激活、阻止下游信号分子磷酸化以及减少胞内游离钙增加、弹性蛋白酶释放和活性氧中间体生成，同时不影响大肠杆菌的吞噬作用。

体内研究

在多种损伤模型中，Reparixin 能够有效减弱炎症反应。此外，它还能显著降低原发性高血压大鼠的收缩压并增加血流量。与普通原发性高血压大鼠相比，在经过 Reparixin 处理的大鼠中，胸主动脉壁厚度明显减小。

反应信息

• 作为产物：
  描述：

  甲基磺酰胺 、 (R)-(-)-布洛芬 在 N,N'-羰基二咪唑 、 1,2-diazabicyclo[5.4.0]undec-7-ene 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 以83%的产率得到repertaxin
  参考文献：
  名称：

  2-Arylpropionic CXC Chemokine Receptor 1 (CXCR1) Ligands as Novel Noncompetitive CXCL8 Inhibitors

  摘要：

  The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNS chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.

  DOI：

  10.1021/jm049082i

文献信息

• 2-Aryl-acetic acids, their derivatives and pharmaceutical compositions containing them
  申请人：Moriconi Alessio

  公开号：US20060223842A1

  公开（公告）日：2006-10-05

  Selected 2-arylacetic acids, their derivatives and pharmaceutical compositions that contain these compounds are useful in inhibiting chemotactic activation of neutrophils (PMN leukocytes) induced by the interaction of Interleukin-8 (IL-8) with CXCR1 and CXCR2-membrane receptors. The compounds are used for the prevention and treatment of pathologies deriving from said activation. In particular, 2(ortho)-substituted arylacetic acids or their derivatives, such as amides and sulfonamides, lack cyclo-oxygenase inhibition activity and are particularly useful in the treatment of neutrophil-dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

  选择的2-芳基乙酸及其衍生物和包含这些化合物的药物组合物对于抑制由白细胞介素-8（IL-8）与CXCR1和CXCR2膜受体相互作用引起的嗜中性粒细胞（PMN白细胞）趋化活化非常有用。这些化合物用于预防和治疗由该活化引起的病理。特别是2（邻）-取代芳基乙酸或其衍生物，例如酰胺和磺酰胺，缺乏环氧合酶抑制活性，特别适用于治疗嗜中性粒细胞依赖性病理，如银屑病、溃疡性结肠炎、黑色素瘤、慢性阻塞性肺疾病（COPD）、大疱性类天疱疮、类风湿性关节炎、特发性纤维化、肾小球肾炎以及缺血再灌注引起的损伤的预防和治疗。
• 2-Arylpropionic Acid Derivatives and Pharmaceutical Compositions Containing Them
  申请人：Allegretti Marcello

  公开号：US20080312293A1

  公开（公告）日：2008-12-18

  The present invention relates to selected (R)-2-phenyl-propionamides and (R)-2-phenyl-sulfonamides with a hydrogen bond acceptor atom/group in a well defined position in the chemical space. These compounds show a surprising potent inhibitory effect on C5a induced human PMN chemotaxis. The compounds of the invention absolutely lack of CXCL8 inhibitory activity. Said compounds are useful in the treatment of pathologies depending on the chemotactic activation of neutrophils and monocytes induced by the fraction C5a of the complement. In particular, the compounds of the invention are useful in the treatment of sepsis, psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of injury caused by ischemia and reperfusion.

  本发明涉及在化学空间中具有氢键受体原子/基团的选定（R）-2-苯基-丙酰胺和（R）-2-苯基-磺酰胺。这些化合物表现出惊人的强烈抑制C5a诱导的人类PMN趋化性的效果。本发明的化合物绝对缺乏CXCL8抑制活性。所述化合物在治疗与补体C5a诱导的中性粒细胞和单核细胞趋化活化有关的病理过程中有用。特别是，在治疗败血症、牛皮癣、类风湿性关节炎、溃疡性结肠炎、急性呼吸窘迫综合征、特发性纤维化、肾小球肾炎以及缺血再灌注损伤的预防和治疗方面，本发明的化合物非常有用。
• Metabolites Of 2-Arylpropionic Acid Derivatives And Pharmaceutical Compositions Containing Them
  申请人：Bertini Riccardo

  公开号：US20090131441A1

  公开（公告）日：2009-05-21

  Metabolites of 2-(R)-4-isobutylarylpropionamides and pharmaceutical compositions containing such compounds are useful in inhibiting the chemotactic activation of neutrophils (PMN leukocytes) induced by the interaction of Interleukin-8 (IL-8) with CXCR1 and CXCR2 membrane receptors. The compounds are used for the prevention and treatment of pathologies deriving from said activation. Notably, these metabolites are devoid of cyclo-oxygenase inhibition activity and are particularly useful in the treatment of neutrophil-dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

  2-(R)-4-异丁基芳基丙酰胺的代谢产物及含有此类化合物的制药组合物在抑制由白细胞介素-8（IL-8）与CXCR1和CXCR2膜受体相互作用引起的中性粒细胞（PMN白细胞）趋化激活方面具有用途。这些化合物用于预防和治疗源于该激活的病理状况。值得注意的是，这些代谢产物不具有环氧合酶抑制活性，并且在治疗依赖于中性粒细胞的病理状况，如银屑病、溃疡性结肠炎、黑色素瘤、慢性阻塞性肺病（COPD）、大疱性类天疱疮、类风湿性关节炎、特发性纤维化、肾小球肾炎以及缺血再灌注所致的损伤的预防和治疗方面特别有用。
• IL-8 INHIBITORS FOR USE IN THE TREATMENT OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
  申请人：Dompé farmaceutici S.p.A.

  公开号：EP3192504A1

  公开（公告）日：2017-07-19

  The present invention relates to IL-8 inhibitor compounds, preferably dual CXCR1/CXCR2 receptor inhibitors, useful in the treatment and/or prevention of chemotherapy-induced peripheral neuropathy.

  本发明涉及IL-8抑制剂化合物，最好是CXCR1/CXCR2双重受体抑制剂，可用于治疗和/或预防化疗引起的周围神经病变。
• IL-8 INHIBITORS FOR USE IN THE TREATMENT AND/OR PREVENTION OF BACTERIAL SECONDARY INFECTIONS
  申请人：Dompé farmaceutici s.p.a.

  公开号：EP3409277A1

  公开（公告）日：2018-12-05

  The present invention relates to IL-8 inhibitor compounds, preferably dual CXCR1/CXCR2 receptor inhibitors, useful in the treatment and/or prevention of secondary bacterial infections, preferably secondary respiratory infections.

  本发明涉及IL-8抑制剂化合物，最好是CXCR1/CXCR2双重受体抑制剂，可用于治疗和/或预防继发性细菌感染，最好是继发性呼吸道感染。