N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide

• 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: N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide
• 化学式: C₅₆H₉₈N₁₆O₁₃
• 分子量: 1203.5
• InChiKey: WQVJHHACXVLGBL-BPJDFBQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  85
• 可旋转键数：
  29
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  491
• 氢给体数：
  18
• 氢受体数：
  18

ADMET

代谢

多粘菌素B的代谢数据很少。在一项研究中，<1%的多粘菌素B通过肾脏排出，且未经代谢。多粘菌素B也出现在胆汁中，同样没有经过代谢过程。

There is little data available for the metabolism of polymyxin B[A176432]. In one study, <1% of polymyxin B was eliminated through the kidneys and it had not been metabolised[A176432]. Polymyxin B has also been found in bile, not having undergone metabolic processes[A176390].

来源:DrugBank

毒理性

• 毒性总结

多粘菌素B可能会导致肾毒性，因为它被认为会在肾小管重吸收后在肾细胞中积累。这种积累可能导致肾细胞凋亡和肾功能下降。最近的研究中，接受多粘菌素B治疗的患者中有31.3%到39.4%出现了急性肾损伤。过量使用多粘菌素B可能导致神经肌肉阻滞，进而引发呼吸暂停、肌肉无力、眩晕、暂时性面部感觉异常、言语不清、血管运动不稳定、视觉障碍、混乱、精神疾病和呼吸停止。还观察到通过减少尿量和增加血尿素氮血清浓度引起的肾衰竭。多粘菌素B过量的治疗方法是停止用药并进行对症治疗。静脉注射甘露醇可能增强肾清除率，血液透析可能管理肾并发症。多粘菌素B在妊娠、哺乳、儿科和老年患者中的安全性尚未确定。除非益处大于风险，否则不应在妊娠期间使用多粘菌素B。哺乳母亲应停止哺乳或停止多粘菌素B治疗，取决于对母亲和孩子的风险。儿科患者应经常监测肾功能，2岁以下儿童无剂量信息。老年患者在治疗前后应评估肾功能。

Nephrotoxicity can occur in patients as polymyxin B is thought to accumulate in renal cells after renal tubular reabsorption[A176390]. This accumulation can lead to apoptosis of renal cells and decrease in renal function[A176399]. In recent studies, acute kidney injury (AKI) has been seen in 31.3% to 39.4% of patients receiving polymyxin B[A176399]. Overdose cases can cause neuromuscular block leading to apnea, muscular weakness, vertigo, transient facial parasthesia, slurred speed, vasomotor instability, visual disturbance, confusion, psychosis, and respiratory arrest[F4151]. Renal failure has also been seen through decreased urine output, and increased serum concentrations of blood urea nitrogen[F4151]. Overdose of polymyxin B is treated by stopping the drug and beginning symptomatic treatment[F4151]. Intravenous administration of mannitol may enhance renal clearance, and hemodialysis may manage renal complications[F4151]. Safety of polymyxin B has not been established in pregnancy, breast feeding, pediatrics, and geriatrics[F4151]. Polymyxin B should no be used in pregnancy unless the benefit outweighs the risk[F4151]. Nursing mothers should either stop nursing or stop polymyxin B treatment depending on the risks to both the mother and child[F4151]. Pediatric patients should be frequently monitored for renal function and no dosing information is available in children under 2 years of age[F4151]. Geriatric patients should have renal function assessed before and regularly during therapy[F4151].

来源:DrugBank

毒理性

• 蛋白质结合

多粘菌素B有79%到92%与蛋白质结合[F4151]。多粘菌素B在循环中可能92%到99%与蛋白质结合，尽管确切的蛋白质尚未被识别[A176420]。

Polymyxin B is 79% to 92% bound to proteins[F4151]. Polymyxin B is likely 92 to 99% protein bound in circulation, though the exact proteins have not been identified[A176420].

来源:DrugBank

吸收、分配和排泄

• 吸收

通过口服途径给药不会导致吸收。

Administration by the oral route does not lead to absorption[A176426].

来源:DrugBank

吸收、分配和排泄

• 消除途径

多粘菌素B主要通过肾小管重吸收和非肾途径消除[A176390,F4151]。人和动物的尿液收集显示，从肾脏排出的多粘菌素B少于5%[A176390]。然而，一份加拿大产品说明书中指出，该药物主要通过肾脏消除，尿液中可回收60%的多粘菌素B[F4151]。这种差异可以通过多粘菌素B在给药和显著消除之间的12至24小时滞后时间来解释[F4151]。非肾消除途径尚未完全了解，但已在内胆汁中检测到多粘菌素B的所有4种成分[A176390]。

Polymyxin B is proposed to be primarily eliminated through renal tubular reabsorption and non-renal pathways[A176390,F4151]. Urine collection in humans and animals show <5% of polymyxin B eliminated from the kidneys[A176390]. However, a Canadian product monograph states the drug is primarily eliminated through the kidneys and that 60% of polymyxin B is recovered in the urine[F4151]. This discrepancy can be explained by the 12 to 24 hour lag time between administration and significant elimination of polymyxin B[F4151]. Non-renal elimination is not well understood but all 4 components of polymyxin B have been detected in bile[A176390].

来源:DrugBank

吸收、分配和排泄

• 分布容积

1室模型估计分布容积为34.3L至47.2L[A176390]。然而，普遍共识是分布容积尚未确定[F4151]。

1 compartment models estimate the volume of distribution to be 34.3L to 47.2L[A176390]. However, the general consensus is that the volume of distribution is yet to be determined[F4151].

来源:DrugBank

吸收、分配和排泄

• 清除

单室模型估计清除率为2.37升/小时至2.5升/小时[A176390]。

1 compartment models estimate clearance to be 2.37L/h to 2.5L/h[A176390].

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide 、 以 水 为溶剂， 反应 93.0h， 生成 H-Thr-Dab-Dab(1)-Dab-Phe-Leu-Dab-Dab-Thr-(1)
  参考文献：
  名称：

  Methods of treating involuntary facial spasms and facial wrinkles

  摘要：

  该发明描述了具有神经肌肉阻滞作用的抗生素、肌肉松弛剂和植物提取物，以及它们的使用方法。这些化合物可以在与肉毒毒素相同的临床环境中使用，并且可以局部使用，因此在应用和使用方面比肉毒毒素具有优势。这些化合物可用于制备药物组合物，用于治疗不自主肌肉痉挛和神经病性疼痛，并用于制备化妆品组合物，用于治疗面部皱纹。还提供了用于治疗和/或化妆应用的工具包。

  公开号：

  US20060093597A1
• 作为产物：
  描述：

  N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide;sulfuric acid 、 Magnesiumoxide 在 盐酸 作用下， 以 水 为溶剂， 反应 17.0h， 生成 N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide
  参考文献：
  名称：

  Endotoxin detoxifying material

  摘要：

  本发明提供了(1)一种含有纤维载体的内毒素解毒材料，该纤维载体上固定有多粘菌素，(2)一种含有载体的内毒素解毒材料，该载体上固定有多粘菌素和一个碱性氮原子，以及(3)一种通过将流体与固定有多粘菌素的内毒素解毒材料接触来从流体中去除内毒素的方法。本发明使得直接而安全地将多粘菌素与血液接触成为可能，并提供了一种治疗内毒素血症或预防内毒素血症的新方法。

  公开号：

  US04771104A1

文献信息

• Endotoxin detoxifying process
  申请人：Toray Industries, Inc.

  公开号：US04661260A1

  公开（公告）日：1987-04-28

  The present invention provides (1) an endotoxin detoxifying material comprising a fibrous carrier to which Polymyxin is fixed, (2) an endotoxin detoxifying material comprising a carrier to which Polymyxin and a basic nitrogen atom are fixed, and (3) a method of removing endotoxin from a fluid by contacting the fluid with the endotoxin detoxifying material comprising a carrier to which Polymyxin is fixed. The present invention makes it possible to contact blood with Polymixin directly and safely and gives a new method of therapy of endotoxemia or prophylaxis of endotoxemia.

  本发明提供了：（1）一种内毒素解毒材料，包括将多粘菌素固定在纤维载体上，（2）一种内毒素解毒材料，包括将多粘菌素和一种碱性氮原子固定在载体上，以及（3）一种通过将流体与将多粘菌素固定在载体上的内毒素解毒材料接触来去除流体中内毒素的方法。本发明使得可以直接安全地将多粘菌素与血液接触，并提供了一种内毒素血症治疗或预防的新方法。
• TREATMENT OF DISEASES CHARACTERIZED BY INFLAMMATION
  申请人：Kaleko Michael

  公开号：US20100120665A1

  公开（公告）日：2010-05-13

  The invention provides, in part, methods, nucleic acids, vectors, proteins and binding molecules that can be used to modulate a pathway such as a complement pathway. These methods and compositions can be utilized, inter alia, for the study and/or treatment of various conditions or diseases related to a complement pathway.

  该发明提供了部分方法、核酸、载体、蛋白质和结合分子，可用于调节通路，例如补体通路。这些方法和组合物可以用于研究和/或治疗与补体通路相关的各种疾病或病症。
• Compounds
  申请人：Novacta Biosystems Limited

  公开号：US20150031602A1

  公开（公告）日：2015-01-29

  Provided are compounds, the use of the said compounds in treatment, for example treatment of microbial infections, particularly by Gram negative bacteria. The compounds are polymyxin-based and are represented by the formula (I): and pharmaceutically acceptable salts thereof, where X is —NHC(O)—, —C(O)—, —OC(O)—, —CH 2 — or —SO 2 —; R 5 represents C 0-12 alkyl(C 4-6 heterocyclyl), or C 2-12 alkyl or C 0-12 alkyl(C 3-8 cycloalkyl). and the alkyl or cycloalkyl bears one, two or three hydroxyl groups, or a —NR 6 R 7 group, or one —NR 6 R 7 group and one or two hydroxyl groups; and R 1 to R 4 and R 6 to R 8 are as defined in the description.

  提供了一些化合物，这些化合物可用于治疗微生物感染，特别是革兰氏阴性菌感染。这些化合物是基于多粘菌素的，并由公式(I)表示：及其药学上可接受的盐，其中X为—NHC(O)—、—C(O)—、—OC(O)—、—CH2—或—SO2—；R5代表C0-12烷基(C4-6杂环基)、C2-12烷基或C0-12烷基(C3-8环烷基)，且烷基或环烷基上带有一个、两个或三个羟基，或一个—NR6R7基团，或一个—NR6R7基团和一个或两个羟基；R1到R4和R6到R8如描述中所定义。
• Polymyxin Derivatives and Their Use in Combination Therapy Together with Different Antibiotics
  申请人：NEW PHARMA LICENCE HOLDINGS LIMITED

  公开号：US20160222061A1

  公开（公告）日：2016-08-04

  Described are compounds of formula (I) for use in combination treatment with a second active agent, such as rifampicin, for example for treatment of a microbial infection. The compound of formula (I) is a polymyxin compound is: where the groups -A-, —R 1 , —R 2 , —R 3 , —R 4 , —R 5 , —R 6 , —R 7 , —R 8 , and —X— are described in detail within the description.

  本文描述了公式（I）的化合物，用于与第二活性剂（例如利福平）联合治疗微生物感染。公式（I）的化合物是一种多粘菌素化合物，其结构如下：其中-A-，—R1，—R2，—R3，—R4，—R5，—R6，—R7，—R8和—X—的各种基团在描述中详细说明。