somatostatin | 38916-34-6

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 其它
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: somatostatin
• 英文别名: somatostatin-14；SS-14；(4R,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37R)-19,34-bis(4-aminobutyl)-37-[[2-[[(2S)-2-amino-1-hydroxypropylidene]amino]-1-hydroxyethylidene]amino]-13,25,28-tribenzyl-6,9,12,15,18,21,24,27,30,33,36-undecahydroxy-10,16-bis[(1R)-1-hydroxyethyl]-31-(2-hydroxy-2-iminoethyl)-7-(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriaconta-5,8,11,14,17,20,23,26,29,32,35-undecaene-4-carboxylic acid
• CAS: 38916-34-6
• 化学式: C₇₆H₁₀₄N₁₈O₁₉S₂
• 分子量: 1637.9
• InChiKey: NHXLMOGPVYXJNR-ATOGVRKGSA-N

物化性质

• 熔点：
  >211°C (dec.)
• 沸点：
  1970.9±65.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)
• 溶解度：
  H2O：1 mg/mL
• 稳定性/保质期：
  常规情况下不会分解，也没有危险反应。

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  115
• 可旋转键数：
  26
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  664
• 氢给体数：
  22
• 氢受体数：
  24

ADMET

代谢

生长抑素能被存在于细胞和血浆中的肽酶迅速降解[A20384]。

Somatostatin is rapidly degraded by peptidase enzymes present in cells and plasma [A20384].

来源:DrugBank

毒理性

• 肝毒性

在预注册的兰瑞肽研究中，血清酶水平没有显著变化，并且没有报告出现临床上明显的急性肝损伤。综合分析报告称，在治疗期间血清ALT、AST或碱性磷酸酶水平没有整体变化，也没有出现具有临床意义的升高。与其它生长抑素类似物一样，长期使用兰瑞肽治疗与胆泥和胆石症的高发生率相关，这可能是由于抑制胆囊收缩力和减少胆汁分泌所致。在长期研究中，20%到33%的使用兰瑞肽治疗的患者发生了胆石症。在某些情况下，会出现有症状的胆囊炎，这可能会伴有血清酶和胆红素的轻至中度升高。然而，大多数与兰瑞肽相关的胆结石是无症状的。与奥曲肽不同，兰瑞肽和其他长效生长抑素类似物并未与临床上明显的肝损伤病例相关联，这种损伤独立于胆石症或胆泥之外，尽管它们的使用范围较窄，并未在许多使用奥曲肽治疗的情况中使用（如门脉高压、静脉曲张出血和患有先天性高胰岛素血症的婴儿）。

In preregistration studies of lanreotide, serum enzyme levels did not change appreciably and there were no reports of clinically apparent acute liver injury. Pooled analyses reported that there were no overall changes in serum ALT, AST or alkaline phosphatase levels during therapy or instances of clinically meaningful elevations with treatment. Prolonged therapy with lanreotide, as with other somatostatin analogues, was associated with a high rate of biliary sludge and cholelithiasis, probably due to inhibition of gall bladder contractility and decrease in bile secretion. In long term studies, cholelithiasis developed in 20% to 33% of lanreotide treated patients. In some instances, symptomatic cholecystitis occurred which can be accompanied by mild-to-moderate elevations in serum enzymes and bilirubin. However, most lanreotide associated gallstones were asymptomatic. Unlike octreotide, lanreotide and other long acting somatostatin analogues have not been liked to cases of clinically apparent liver injury, independent of cholelithiasis or biliary sludge, although they have had more limited use and have not been used in many of the clinical situations that were treated with octreotide (portal hypertension, variceal hemorrhage and infants with congenital hyperinsulinemia).

来源:LiverTox

毒理性

• 肝毒性

轻微的、短暂的、无症状的血清转氨酶水平升高发生在接受奥曲肽治疗的小部分患者中，有些人转氨酶水平升高持续存在，并随着时间的推移而恶化，可能需要停药。此外，已经描述了几例归因于奥曲肽的急性、临床上明显的肝损伤。发病通常在开始治疗后的1到6个月内，并且随着剂量增加，损伤可能更频繁。与奥曲肽治疗相关的肝损伤大多数是无症状和非黄疸的，以血清ALT和AST显著升高为特征，血清碱性磷酸酶、GGT和胆红素正常或接近正常。然而，在某些情况下，尤其是在重新挑战时，会出现黄疸。尚无急性肝衰竭或消失性胆管综合征与奥曲肽相关的实例，并且损伤的特征之一是停止注射或输注后迅速改善。在连续输注高剂量奥曲肽治疗的新生儿和婴儿中，有几例报告显示，停止治疗后转氨酶显著升高并迅速改善。 奥曲肽导致胆囊收缩力抑制和胆汁分泌减少，长期治疗与胆结石形成的高发生率相关。在前瞻性研究中，接受维持性奥曲肽治疗的肢端肥大症患者中，有25%至65%的患者通过超声检查发现胆结石，其中一部分患者发展为有症状的胆石症，需要住院和胆囊切除术。即使在胆囊切除术后，胆总管和肝内胆管中也可能形成胆固醇结石，导致症状、败血症发作和需要部分肝切除。使用熊去氧胆酸治疗似乎不能预防奥曲肽治疗期间的胆结石形成，尽管可能有帮助。奥曲肽还与急性胰腺炎有关，这可能是由于它对胃肠道激素释放的抑制作用，尽管其他病例可能是由于胆结石通过和胰腺导管阻塞。 可能性评分：C（可能是临床上明显肝损伤的原因）。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in a small proportion of patients receiving octreotide, and in some individuals the elevations are persistent and worsen over time and may require drug discontinuation. In addition, several instances of acute, clinically apparent liver injury attributable to octreotide have been described. The onset is generally within 1 to 6 months of starting therapy and injury may be more frequent with higher doses. Most cases of liver injury associated with octreotide therapy have been asymptomatic and anicteric, and marked by prominent elevations in serum ALT and AST with normal or near normal serum alkaline phosphatase, GGT and bilirubin. In some instances, however, jaundice has arisen, particularly with rechallenge. There have been no instances of acute liver failure or vanishing bile duct syndrome associated with octreotide, and a characteristic feature of the injury is the rapidity of improvement upon stopping the injections or infusions. Several instances of marked aminotransferase elevations with rapid improvements on stopping have been reported in newborns and infants with congenital hyperinsulinemia who were treated with continuous infusions of high doses of octreotide. Octreotide causes inhibition of gall bladder contractility and decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 25% and 65% of patients with acromegaly treated with maintenance octreotide developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts causing symptoms, episodes of sepsis and need for partial hepatic resection. Therapy with ursodiol does not appear to prevent gallstone formation during octreotide therapy, although it may help. Octreotide has also been associated with acute pancreatitis, which may be due to its inhibitory effect on gastrointestinal hormone release, although other cases may be secondary to passage of gall bladder stones and pancreatic duct obstruction. Likelihood score: C (probable cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 肝毒性

轻度的、短暂的、无症状的血清转氨酶水平升高在接受帕西瑞肽LAR治疗的患者中发生率为高达29%，但超过正常上限5倍以上的升高是罕见的（ 帕西瑞肽会导致胆囊收缩能力的抑制和胆汁分泌的减少，长期治疗与胆结石形成的高发生率有关。在前瞻性研究中，接受维持帕西瑞肽治疗一年到两年的肢端肥大症患者中，有20%到30%的患者通过超声检查发现胆结石，其中一部分患者发展为有症状的胆石症，需要住院并进行胆囊切除术。即使在胆囊切除术后，胆固醇结石也可能在奥曲肽治疗期间在胆总管和肝内胆管中形成，这可能导致症状和肝功能测试异常。使用熊去氧胆酸治疗似乎并不能预防与奥曲肽治疗相关的胆结石形成，尽管它可能有所帮助。 可能性评分：E*（未经证实但疑似罕见的临床明显肝胆损伤原因）。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in up to 29% of patients receiving pasireotide LAR, but elevations above 5 times the upper limit of normal are rare ( Pasireotide causes inhibition of gall bladder contractility and a decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 20% and 30% of patients with acromegaly treated with maintenance pasireotide for one to two years developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts during somatostatin analogue therapy which can cause symptoms and liver test abnormalities. Therapy with ursodiol does not appear to prevent gallstone formation related to somatostatin analogue therapy, although it may help. Likelihood score: E* (unproven but suspected rare cause of clinically apparent hepatobiliary injury).

来源:LiverTox

毒理性

• 毒性总结

数据不可用。

Data is not available.

来源:DrugBank

毒理性

• 蛋白质结合

这项药代动力学数据与此无关。

This pharmacokinetic data is irrelevant.

来源:DrugBank

吸收、分配和排泄

• 吸收

这项药代动力学数据与此无关。

This pharmacokinetic data is irrelevant.

来源:DrugBank

吸收、分配和排泄

• 消除途径

作为多肽链，生长抑素主要通过肽酶酶的代谢消除[A20384]。

As a polypeptide chain, somatostatin is primarily eliminated via metabolism by peptidase enzymes [A20384].

来源:DrugBank

吸收、分配和排泄

• 分布容积

这项药代动力学数据与此无关。

This pharmacokinetic data is irrelevant.

来源:DrugBank

吸收、分配和排泄

• 清除

静脉注射3H标记的内源性生长抑素后，总体清除率约为50毫升/分钟[A32596]。在人类中，该值计算高达3000毫升/分钟，这大大超过了肝血流量。这表明在循环和其他组织中快速酶解是消除的关键途径[A32596]。

Following intravenous administration of 3H-labeld endogenous somatostatin, the total body clearance was approximately 50 mL/min [A32596]. In man, the value was calculated to be as high as 3000 mL/minutes, which is greatly exceeds the hepatic blood flow. This suggests that rapid enzymatic breakdown in the circulation and other tissues serves as a critical route of elimination [A32596].

来源:DrugBank

安全信息

• WGK Germany：
  3
• 危险品标志：
  Xi
• 危险类别码：
  R36/37/38
• RTECS号：
  WF8751700
• 储存条件：
  密封存储，在-18 ℃下保存

制备方法与用途

醋酸生长抑素概述

醋酸生长抑素，即生长激素释放抑制因子，是人体内的一种内源性调节激素。它对多种生理功能具有广泛的抑制作用。

应用

临床常用于治疗严重急性食管静脉曲张破裂出血、急性胃或十二指肠溃疡出血、急性糜烂性胃炎或出血性胃炎、胰腺、胆道和肠瘘的辅助治疗，以及糖尿病酮症酸中毒的辅助治疗。

作用机理

醋酸生长抑素通过内分泌、外分泌、神经性分泌及旁分泌等多种途径发挥其多样性和特异性的作用。它能够抑制生长激素、促甲状腺素、胰岛素、胰高血糖素、胰多肽、胆囊收缩素和胃泌素等激素的分泌，还能抑制胃酸、肝胆汁分泌，并影响胃肠道吸收、运动及血流。同时，它对胰腺、肝脏和胃细胞具有保护作用。

生理功能

1. 抑制腺垂体分泌生长素、催乳素、促甲状腺素和促肾上腺皮质激素。
2. 抑制胰腺和胃肠道内分泌细胞分泌胰岛素、胰高血糖素、血管活性肠肽、胰多肽、胃泌素、胆囊收缩素和胃动素。
3. 抑制胰腺和胃肠道外分泌腺分泌胰液碳酸氢盐、胰酶类、水分、胃酸及造血内因子、胃蛋白酶等。
4. 抑制胃肠道运动和对葡萄糖、氨基酸、甘油三酯的吸收，并促进离子的转运。
5. 抑制内脏血流。
6. 抑制细泡细胞增殖和肿瘤生长。
7. 对胃粘膜细胞及肝细胞具有适应性保护作用。
8. 抑制中枢神经系统活性。
9. 激活鸦片受体。
10. 抑制或刺激组胺释放。

药代动力学

静脉注射后，半衰期约为1.1～3分钟。在肝病患者中为1.2～8分钟，在慢性肾功能不全患者中为2.6～4.9分钟。以75μg/h的速度静滴时，15分钟后达到稳定浓度1250μg/L，代谢清除率约为1L/min，半衰期为2.7分钟。本品在肝内迅速代谢，主要经尿排泄，4小时后排出40%，24小时后排出70%。

用法用量

• 急性严重上消化道出血：以250μg/h的速度连续静脉滴注；必要时先给250μg静脉推注，时间不少于3分钟。止血后再连续给药48～72小时，总疗程不超过120小时。
• 预防胰腺炎术后并发症：手术开始时以250μg/h速度静脉滴注，持续至术后第5日。
• 急性胰腺炎：以250μg/h速度静脉滴注5～7天。
• 糖尿病酮症酸中毒：以100～500μg/h速度静脉滴注给药；同时结合胰岛素治疗。

注意与禁忌

• 连续静脉给药过程中，应不断滴注，换药时间不能超过1分钟。如间断时间长，需重新给予250μg的冲击量，再以250μg/h的速度滴注。
• 本品不适于动脉出血。
• 治疗急性胰腺炎应在确诊后立即给药。
• 注入本品可有短暂的恶心、面红、腹痛、腹泻和血糖轻度变化。本品应保存在2～8℃低温条件下。

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%

反应信息

• 作为反应物：
  描述：

  somatostatin 在 碳酸氢铵 、 trypsin 作用下， 以 aq. buffer 为溶剂， 反应 2.0h， 生成 N-L-alanylglycyl-S-(((R)-2-((S)-2-((2S,3R)-2-((S)-2-((2S,3R)-2-amino-3-hydroxybutanamido)-3-phenylpropanamido)-3-hydroxybutanamido)-3-hydroxypropanamido)-2-carboxyethyl)thio)-L-cysteinyl-L-lysine
  参考文献：
  名称：

  气相肽亚磺酰基自由基离子：形成和单分子解离

  摘要：

  在大气压 (AP) 下形成了多种在半胱氨酸侧链具有明确自由基位点的肽亚磺酰基 (RSO•) 离子，将其采样到质谱仪中，并通过碰撞诱导解离 (CID) 进行研究。自由基离子的形成是基于氧化自由基与包含单链间二硫键或纳米电喷雾电离 (nanoESI) 产生的游离硫醇基团的肽离子之间的 AP 反应。自由基引发的反应允许在形成肽自由基离子方面具有很大的灵活性，而不受离子极性（质子化或去质子化）或电荷状态（单电荷或多电荷）的影响。在三重四极杆/线性离子阱质谱仪上，以正离子或负离子模式对超过 20 个肽亚磺酰基自由基离子进行低能量碰撞激活。自由基和电荷导向碎裂途径之间的竞争在很大程度上受到移动质子存在的影响。对于质子迁移率降低（即单质子化，含有碱性氨基酸残基）的肽亚磺酰基离子，损失 62 Da (CH2 SO)，一个自由基引发的解离通道，占主导地位。对于具有移动质子的系统，该通道被抑制，而电荷导向的酰

  DOI：

  10.1007/s13361-012-0465-0
• 作为产物：
  描述：

  (2S)-2-[[hydroxy-[(2-methylpropan-2-yl)oxy]methylidene]amino]-N-[2-hydroxy-2-[[(4R,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37R)-13,25,28-tribenzyl-4-[[2,4-di(docosoxy)phenyl]methoxycarbonyl]-6,9,12,15,18,21,24,27,30,33,36-undecahydroxy-19,34-bis[4-[[hydroxy-[(2-methylpropan-2-yl)oxy]methylidene]amino]butyl]-31-(2-hydroxy-2-trityliminoethyl)-22-[[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]methyl]-10,16-bis[(1R)-1-[(2-methylpropan-2-yl)oxy]ethyl]-7-[(2-methylpropan-2-yl)oxymethyl]-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriaconta-5,8,11,14,17,20,23,26,29,32,35-undecaen-37-yl]imino]ethyl]propanimidic acid 在 三异丙基硅烷 、 三氟乙酸 作用下， 以 水 为溶剂， 以95%的产率得到somatostatin
  参考文献：
  名称：

  可溶性载体辅助的电化学反应：在阳极二硫键形成中的应用

  摘要：

  可溶性支持物辅助技术已成功应用于电化学反应，导致形成了阳极二硫键。与支持物结合的肽可溶于电解质溶液，从而使电子在电极表面转移。反应完成后，通过用不良溶剂简单稀释反应混合物，以沉淀形式回收结合了载体的产物。

  DOI：

  10.1021/ol302863r

文献信息

• Reversible covalent linkage of functional molecules
  申请人：Smith Mark

  公开号：US09295729B2

  公开（公告）日：2016-03-29

  The present invention relates to the use of a compound containing a moiety of formula (I) as a reagent for linking a compound of formula R1—H which comprises a first functional moiety of formula F1 to a second functional moiety of formula F2 wherein X, X′, Y, R1, F1 and F2 are as defined herein. The present invention also provides related processes and products. The present invention is useful for creating functional conjugate compounds, and specifically conjugates in which at least one of the constituent molecules carries a thiol group.

  本发明涉及使用含有式(I)的基团的化合物作为将具有式F1的第一功能基团的化合物R1-H与具有式F2的第二功能基团连接的试剂 其中X、X'、Y、R1、F1和F2如本文所定义。本发明还提供相关的工艺和产品。本发明适用于制备功能共轭化合物，特别是至少一种组分分子携带硫醇基团的共轭物。
• Aryloxymaleimides for cysteine modification, disulfide bridging and the dual functionalization of disulfide bonds
  作者：Cristina Marculescu、Hanno Kossen、Rachel E. Morgan、Patrick Mayer、Sally A. Fletcher、Berend Tolner、Kerry A. Chester、Lyn H. Jones、James R. Baker

  DOI：10.1039/c4cc02107j

  日期：——

  Aryloxymaleimides represent ‘next generation maleimides’ of attenuated reactivity. We demonstrate their use in establishing novel bioconjugation procedures at disulfide bonds.

  Aryloxymaleimides代表了反应性减弱的“下一代马来酰亚胺”。我们展示了它们在建立新的二硫键生物偶联程序中的应用。
• Programming Bioactive Architectures with Cyclic Peptide Amphiphiles
  作者：Seah Ling Kuan、Tao Wang、Marco Raabe、Weina Liu、Markus Lamla、Tanja Weil

  DOI：10.1002/cplu.201500218

  日期：2015.8

  synthesis of cyclic peptide amphiphiles of the hormone somatostatin (SST) with tunable lipophilic tails to program bioactive nanoarchitectures. A novel bis-alkylation reagent is synthesized that facilitates the functionalization of SST with a thiol anchor. Different hydrophobic moieties are introduced inspired by a biomimetic palmitoylation approach which opens access to cyclic peptide amphiphiles that

  我们提供了一种通用的方法，用于合成具有可调亲脂性尾巴的激素生长抑素（SST）的环状肽两亲物，以对生物活性纳米结构进行编程。合成了新颖的双烷基化试剂，其促进了具有硫醇锚定的SST的功能化。在仿生棕榈酰化方法的启发下，引入了不同的疏水部分，该方法使人们可以接触显示出丰富的自组织和细胞膜相互作用的环状肽两亲物。
• Bis-sulfide bioconjugates for glutathione triggered tumor responsive drug release
  作者：Tao Wang、David Y. W. Ng、Yuzhou Wu、Jessica Thomas、Thuy TamTran、Tanja Weil

  DOI：10.1039/c3cc47003b

  日期：——

  The reaction of bis-sulfone conjugation reagents with disulfide bonds allows the site-specific modification of various peptides and proteins. Herein, we present the intracellular disintegration of bis-sulfide containing somatostatin bioconjugates under controlled, tumor-relevant glutathione levels. GSH responsive release is demonstrated, which offers high potential for designing tumor responsive therapeutics.

  双硫砜偶联试剂与二硫键的反应能够对各种肽和蛋白质进行位点特异性修饰。在此，我们展示了含有双硫键的生长抑素生物共轭物在受控且与肿瘤相关的谷胱甘肽水平下的细胞内解体。谷胱甘肽响应性释放被证实，这为设计肿瘤响应性治疗药物提供了巨大潜力。
• A Disulfide Intercalator Toolbox for the Site-Directed Modification of Polypeptides
  作者：Tao Wang、Yuzhou Wu、Seah Ling Kuan、Oliver Dumele、Markus Lamla、David Y. W. Ng、Matthias Arzt、Jessica Thomas、Jan O. Mueller、Christopher Barner-Kowollik、Tanja Weil

  DOI：10.1002/chem.201403965

  日期：2015.1.2

  A disulfide intercalator toolbox was developed for site‐specific attachment of a broad variety of functional groups to proteins or peptides under mild, physiological conditions. The peptide hormone somatostatin (SST) served as model compound for intercalation into the available disulfide functionalization schemes starting from the intercalator or the reactive SST precursor before or after bioconjugation

  开发了一种二硫键嵌入剂工具箱，用于在温和的生理条件下将各种官能团定点连接到蛋白质或肽上。肽激素生长抑素（SST）用作模型化合物，可在生物缀合之前或之后从嵌入剂或反应性SST前体插入到可用的二硫键官能化方案中。获得了四唑-SST衍生物，该衍生物在哺乳动物细胞中经历了光诱导的环加成反应，并通过活细胞成像进行了监测。