(2S)-2-[[(3aS,7aS)-1-[2-[(2S)-2-[[(2S)-2-[[2-[[(4R)-1-[1-[2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-yl-propan | 130308-48-4

• 物质功能分类: 生物化工 - 多肽
• 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: (2S)-2-[[(3aS,7aS)-1-[2-[(2S)-2-[[(2S)-2-[[2-[[(4R)-1-[1-[2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-yl-propan
• 英文别名: (2S)-2-[[(3aS,7aS)-1-[2-[(2S)-2-[[(2S)-2-[[2-[[(4R)-1-[1-[2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid
• CAS: 130308-48-4
• 化学式: C₅₉H₈₉N₁₉O₁₃S
• 分子量: 1304.5
• InChiKey: QURWXBZNHXJZBE-MCDGZUPGSA-N

物化性质

• 密度：
  1.60±0.1 g/cm3(Predicted)
• 溶解度：
  水：100.0（最大浓度 mg/mL）；76.66（最大浓度 mM）
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  -6.4
• 重原子数：
  92
• 可旋转键数：
  30
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  552
• 氢给体数：
  15
• 氢受体数：
  18

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于艾卡坦特排泄到母乳中的信息。由于艾卡坦特是一种分子量为1305 Da的蛋白质分子，母乳中的含量可能非常低。它还可能在婴儿的胃肠道中被部分破坏，并且婴儿的吸收可能很少。据报道，有一名病人在哺乳期间安全地使用了该药物。在剂量后的6小时内等待哺乳应该可以最小化排泄到母乳中的药物量。 对哺乳婴儿的影响：一名有遗传性血管性水肿的妇女在哺乳婴儿4个月大时开始根据需要使用艾卡坦特30毫克皮下注射治疗遗传性血管性水肿，并在服用艾卡坦特的同时继续哺乳了1年。剂量是在婴儿最长的睡眠期之前注射的，至少在剂量后的6小时后才恢复哺乳。在面部和颈部肿胀以及腹痛的情况下，艾卡坦特会立即自行给药，并给予配方奶而不是母乳。在两年后的第二次怀孕中，她使用C1酯酶抑制剂直到婴儿1个月大，然后她恢复了艾卡坦特治疗。 对哺乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the excretion of icatibant into breastmilk. Because icatibant is a protein molecule with a molecular weight of 1305 Da, the amount in milk is likely to be very low. It is also likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. One patient reportedly used the drug safely during breastfeeding. Waiting 6 hours after a dose before breastfeeding should minimize the amount of drug excreted into breastmilk. ◉ Effects in Breastfed Infants:A woman with hereditary angioedema began using icatibant 30 mg subcutaneously as needed for hereditary angioedema attacks when her breastfed infant was 4 months of age and continued breastfeeding for 1 year while taking icatibant. Doses were injected at night before the infant’s longest sleep period and breastfeeding was not resumed until at least 6 hours after a dose. In cases of swelling of the face and neck and abdominal pain, icatibant was immediately self-administered, and formula was given instead of breastmilk. In her second pregnancy 2 years later, she used C1 esterase inhibitor until the infant was 1 month of age, when she resumed icatibant therapy. . ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

安全信息

• WGK Germany：
  3

制备方法与用途

艾替班特的作用

艾替班特是一种对缓激肽B2受体选择性竞争性拮抗剂，其亲和力与缓激肽相似。遗传性血管水肿是由C1-酯酶抑制剂的缺乏或功能失调引起的一种疾病，而缓激肽作为一种血管扩张剂，被认为是导致局部肿胀、炎症及疼痛等HAE特征症状的主要因素。艾替班特通过抑制缓激肽与B2受体结合，用于治疗HAE急性发作的症状。此外，它还具有潜在的治疗哮喘、肝硬化及其他类型血管性水肿的可能性。

艾替班特的用途

艾替班特是一种合成多肽（包含10个氨基酸），其结构与缓激肽相似，是强效的选择性缓激肽B2受体拮抗剂。通过阻止缓激肽与其B2受体结合，艾替班特能够有效治疗急性发作期HAE患者的症状。

艾替班特的生物活性

IcatiBAnt（HOE-140）是一种有效的、特异性的缓激肽B2受体拮抗剂，其IC50和Ki值分别为1.07 nM和0.798 nM。

体外研究

在体外实验中，IcatiBAnt（10-30 μM）能够增强angiotensin III的作用但对由angiotensin AT1受体介导的收缩没有影响；同时，它还能增强Lys-des-Arg9-bradykinin的效果而不会影响des-Arg9-bradykinin。

体内研究

在一项体内实验中，IcatiBAnt（0.3或1.5 mg/kg）以皮下注射的方式每日两次给药于CBA/J (H-2k)雌性小鼠。结果显示，在剂量为1.5 mg/kg和0.3 mg/kg时，大肠的长度分别达到93.6±6.8 mm和94.0±4.1 mm，表现出显著的预防作用，防止了大肠缩短。

参考质量标准

• 外观：白色粉末
• 纯度（HPLC）≥98.0%
• 单杂≤1.0%
• 醋酸根含量5.0%～12.0%
• 水分含量≤10.0%
• 肽含量≥80.0%

文献信息

• Modulation of Cellular Migration
  申请人：THE UAB RESEARCH FOUNDATION

  公开号：US20140248291A1

  公开（公告）日：2014-09-04

  Methods, kits, and compositions are provided for addressing cancer through the interaction of bradykinin (BK) and the bradykinin-2-receptor (B2R). This interaction controls cellular invasion, as has been unexpectedly observed in glioma cells, A composition is provided for the treatment of cancer by disrupting this interaction using an inhibitor or BK or B2R that can. be administered to the subject. Diagnostic processes are provided, involving measuring levels of BK or B2R to determine the potential for cancer (or to determine the invasive potential of a given cancer). Modulators of BK. and B2R may be used to modulate cellular migration, both in vivo and in vitro. Potential modulators of cellular migration can be screened by measuring the effect of the potential modulator on BK or B2R,
• SYNTHESIS OF ICATIBANT
  申请人：BIOCON LIMITED

  公开号：US20200247841A1

  公开（公告）日：2020-08-06

  The present invention relates to the efficient solid-phase synthesis of Icatibant represented by Formula (I). The present invention relates to an efficient process for the preparation of Icatibant by sequential coupling employing solid phase approach. It involves sequential coupling of protected amino acids to prepare Icatibant. The present invention also involves the usage of inorganic salts during the coupling, wash with HOBt in DMF solution after Fmoc-deprotection step to ensure complete removal of piperidine and reactions are going for completion, and thus avoid addition/deletion sequences and also improve the process yield.