生长抑素

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 中文名称: 生长抑素
• 英文名称: somatostatin 14
• 英文别名: 19,34-bis(4-aminobutyl)-37-[[2-[(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(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
• 化学式: C₇₆H₁₀₄N₁₈O₁₉S₂
• 分子量: 1637.9
• InChiKey: NHXLMOGPVYXJNR-UHFFFAOYSA-N

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

毒理性

• 肝毒性

在兰瑞肽的预注册研究中，血清酶水平没有显著变化，并且没有临床明显的急性肝损伤的报告。汇总分析报告称，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，长期使用兰瑞肽与胆泥和胆石症的高发生率相关，这可能是由于胆囊收缩性抑制和胆汁分泌减少所致。在长期研究中，20%到33%的兰瑞肽治疗患者发生了胆石症。在某些情况下，会出现有症状的胆囊炎，可能伴有血清酶和胆红素的轻中度升高。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没有与临床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，并且没有用于许多曾用奥曲肽治疗的临床情况（如门脉高压、静脉曲张出血和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

轻度的、短暂的、无症状的血清转氨酶水平升高在接受奥曲肽治疗的患者中小部分出现，并且一些人升高情况持续并随时间恶化，可能需要停药。此外，已经描述了几例急性、临床上明显的肝损伤，归因于奥曲肽。发病通常在开始治疗后的1到6个月内，并且随着剂量较高，损伤可能更频繁。与奥曲肽治疗相关的肝损伤大多数病例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，尤其是重新用药后，出现了黄疸。尚无急性肝衰竭或消失胆管综合征与奥曲肽相关的实例，并且损伤的特征是停止注射或输注后迅速改善。在接受高剂量奥曲肽连续输注的先天性高胰岛素血症的新生儿和婴儿中，已经报告了几例在停止用药后转氨酶显著升高并迅速改善的情况。 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，并且一部分患者出现了需要住院和胆囊切除术的症状性胆石症。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术。尽管熊去氧胆酸治疗可能有所帮助，但它似乎并不能预防奥曲肽治疗期间的胆结石形成。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的继发结果。 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，高达29%，但高于正常上限5倍的升高是罕见的（ 帕西瑞肽会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，接受维持帕西瑞肽治疗的肢端肥大症患者中，有20%至30%的患者在一到两年内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防止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

反应信息

• 作为反应物：
  描述：

  氯化钠 、 生长抑素 生成 somatostatin
  参考文献：
  名称：

  Topical ophthalmic peptide formulation

  摘要：

  一种肽类的局部眼科制剂及其用于治疗和/或局部预防眼部疾病，尤其是后段眼疾病的用途。

  公开号：

  US09216208B2

文献信息

• [EN] MULTIDENTATE BIFUNCTIONAL CHELATING AGENTS FOR RADIONUCLIDE COMPLEXATION IN DIAGNOSTICS AND THERAPY<br/>[FR] AGENTS BIFONCTIONNELS MULTIDENTATES DE CHÉLATION POUR LA COMPLEXATION DE RADIONUCLÉIDES EN DIAGNOSTIC ET EN THÉRAPIE
  申请人：UNIV ZUERICH

  公开号：WO2015140212A1

  公开（公告）日：2015-09-24

  The invention relates to octadentate ligands of a general formula R1 - D - X - D - X - D - X - D - E - R2, wherein D is C(O)N(OH) or N(OH)C(O), pyrimidinone or pyridinone, each X independently of any other X is a saturated or partially unsaturated, substituted or unsubstituted linker comprising 8-11 atoms selected from any of N, C, O; R1 is alkyl, cycloalkyl, arene, or heteroarene, E is a saturated or partially unsaturated, substituted or unsubstituted chain comprising 1 - 50 atoms and R2 is a moiety capable of selectively binding to a biomolecule, or a nanoparticle. The invention further relates to complexes of the ligand, particularly radionuclides and their use in radioimmunotherapy and imaging.

  该发明涉及一般公式为R1 - D - X - D - X - D - X - D - E - R2的八齿配体，其中D为C(O)N(OH)或N(OH)C(O)，嘧啶酮或吡啶酮，每个X独立于其他X，是由N、C、O中的任意8-11个原子构成的饱和或部分不饱和、取代或未取代的连接基；R1为烷基、环烷基、芳烃或杂环烃；E为由1-50个原子构成的饱和或部分不饱和、取代或未取代链；R2为能够选择性结合生物分子或纳米颗粒的基团。该发明还涉及配体的络合物，特别是放射性同位素及其在放射免疫治疗和成像中的应用。
• Conjugates of disorazoles and their derivatives with cell-binding molecules, novel disorazole derivatives, processes of manufacturing and uses thereof
  申请人：AEterna Zentaris GmbH

  公开号：EP1900742A1

  公开（公告）日：2008-03-19

  The present invention provides conjugates of disorazoles and their derivatives with cell-binding molecules, such as peptides, proteins, hormones, blood proteins and antibodies. The present invention further provides novel disorazole derivatives and processes of manufacturing such conjugates and disorazole derivatives. These compounds can be used as medicaments for the treatment of physiological and/or pathophysiological conditions in mammals, in particular for the treatment of various tumors.

  本发明提供了二氢异菊烯酮及其衍生物与细胞结合分子（如肽、蛋白质、激素、血液蛋白和抗体）结合的共轭物。本发明还提供了新的二氢异菊烯酮衍生物及制造这些共轭物和二氢异菊烯酮衍生物的方法。这些化合物可用作治疗哺乳动物的生理和/或病理状况，特别是治疗各种肿瘤的药物。
• TOPICAL OPHTHALMIC PEPTIDE FORMULATION
  申请人：Simó Canonge Rafael

  公开号：US20130210728A1

  公开（公告）日：2013-08-15

  A topical ophthalmic formulation of peptides and their use for the treatment and/or local prevention of ocular diseases, preferably posterior segment eye diseases.

  一种肽类局部眼科制剂及其用于治疗和/或局部预防眼部疾病，尤其是后部眼部疾病的用途。
• Phenylpropynones as Selective Disulfide Rebridging Bioconjugation Reagents
  作者：Diederick Maes、Marvin Nicque、Mehwish Iftikhar、Johan M. Winne

  DOI：10.1021/acs.orglett.3c04160

  日期：2024.2.2

  linkage joining two thiols. The reactivity of various Michael-alkyne reagents is compared in this chemoselective, atom economical, and non-oxidative cross-linking of two thiols. The stability and chemical reactivity of the dithioacetal links are studied, and the utility of the disulfide targeting bioconjugation methodology is shown by the selective rebridging of native cyclic peptides after the reductive

  简单的 1-苯基丙酮在缓冲介质中与硫醇发生选择性双硫杂迈克尔加成，产生连接两个硫醇的有趣的二硫缩醛键。在两种硫醇的化学选择性、原子经济性和非氧化性交联中比较了各种迈克尔-炔试剂的反应性。研究了二硫缩醛连接的稳定性和化学反应性，并通过在二硫键还原断裂后选择性地重新桥接天然环肽，展示了二硫键靶向生物共轭方法的实用性。
• Multidentate bifunctional chelating agents for radionuclide complexation in diagnostics and therapy
  申请人：UNIVERSITAT ZURICH

  公开号：US11033642B2

  公开（公告）日：2021-06-15

  The invention relates to octadentate ligands of a general formula R1-D-X-D-X-D-X-D-E-R2, wherein D is C(O)N(OH) or N(OH)C(O), pyrimidinone or pyridinone, each X independently of any other X is a saturated or partially unsaturated, substituted or unsubstituted linker comprising 8-11 atoms selected from any of N, C, O; R1 is alkyl, cycloalkyl, arene, or heteroarene, E is a saturated or partially unsaturated, substituted or unsubstituted chain comprising 1-50 atoms and R2 is a moiety capable of selectively binding to a biomolecule, or a nanoparticle. The invention further relates to complexes of the ligand, particularly radionuclides and their use in radioimmunotherapy and imaging.

  本发明涉及通式为 R1-D-X-D-X-D-X-D-E-R2 的八齿配体，其中 D 是 C(O)N(OH)或 N(OH)C(O)、嘧啶酮或吡啶酮，每个 X 独立于任何其他 X 是饱和或部分不饱和、取代或未取代的连接体，包括 8-11 个选自 N、C、O 中任何一种的原子；R1 是烷基、环烷基、炔基或杂芳基，E 是由 1-50 个原子组成的饱和或部分不饱和、取代或未取代的链，R2 是能够选择性地与生物大分子或纳米粒子结合的分子。本发明还涉及配体的复合物，特别是放射性核素及其在放射免疫治疗和成像中的应用。