帕瑞肽 | 396091-73-9

• 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
• 中文名称: 帕瑞肽
• 中文别名: 帕瑞肽标准品；帕西瑞肽
• 英文名称: pasireotide
• 英文别名: Signifor；SOM230；[(3S,6S,9S,12R,15S,18S,20R)-9-(4-aminobutyl)-3-benzyl-12-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-15-phenyl-6-[(4-phenylmethoxyphenyl)methyl]-1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] N-(2-aminoethyl)carbamate
• CAS: 396091-73-9
• 化学式: C₅₈H₆₆N₁₀O₉
• 分子量: 1047.22
• InChiKey: VMZMNAABQBOLAK-DBILLSOUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  77
• 可旋转键数：
  18
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  281
• 氢给体数：
  9
• 氢受体数：
  11

ADMET

代谢

新陈代谢是最小的。

Metabolism is minimal.

来源:DrugBank

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

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：对帕西瑞肽排入母乳的情况尚未进行研究。然而，由于其分子量高达1047道尔顿，它很可能不易排入母乳，并且作为一种肽类物质，它可能会在婴儿的胃肠道中被消化。它不太可能达到婴儿血清中的临床重要水平。但是，制造商表示哺乳期母亲不应使用帕西瑞肽。建议使用其他药物。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:The excretion of pasireotide into breastmilk has not been studied. However, because it has a high molecular weight of 1047 daltons it is likely to be poorly excreted into breastmilk and it is a peptide that is likely digested in the infant's gastrointestinal tract. It is unlikely to reach the clinically important levels in infant serum. However, the manufacturer states that nursing mothers should not use pasireotide. An alternate drug is preferred. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

血浆蛋白结合率为88%。

Plasma protein binding is 88%.

来源:DrugBank

吸收、分配和排泄

• 吸收

帕西瑞肽的血浆峰浓度出现在0.25-0.5小时。在单次和多次给药后，Cmax和AUC呈现出剂量成正比的增加。

The peak plasma concentration of pasireotide occurs in 0.25-0.5 hours. After administration of single and multiple doses, there is dose-proportionoal increases in Cmax and AUC.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Pasireotide主要通过肝脏清除（胆汁排泄）（约48%）以及少量的肾脏清除（约7.63%）来消除。

Pasireotide is eliminated mostly by hepatic clearance (biliary excretion)(about 48%) with some minor renal clearance (about 7.63%).

来源:DrugBank

吸收、分配和排泄

• 分布容积

帕西瑞肽分布广泛，其分布体积超过100升。

Pasireotide is widely distributed and has a volume of distribution of >100L.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康患者中清除率约为7.6升/小时，而在库欣病患者中清除率约为3.8升/小时。

The clearance in healthy patient is ~7.6 L/h and in Cushing’s disease patients is ~3.8 L/h.

来源:DrugBank

反应信息

• 作为产物：
  描述：

  cyclo[Pro(4-OCO-NH-CH2-CH2-NH-Boc)-Phg-D-Trp(BoC)-Lys(Boc)-Tyr(Bzl)-Phe] 在 三异丙基硅烷 、 三氟乙酸 作用下， 以 水 为溶剂， 反应 1.0h， 生成 帕瑞肽
  参考文献：
  名称：

  [EN] NOVEL PROCESS FOR THE PREPARATION OF PASIREOTIDE
  [FR] NOUVEAU PROCÉDÉ DE PRÉPARATION DE PASIRÉOTIDE

  摘要：

  本发明涉及一种用于制备化学式11的帕西瑞肽的新型工艺。该发明还涉及一种化学式8的新型中间化合物及其制备工艺，该中间化合物用于制备化合物11。

  公开号：

  WO2016207912A1

文献信息

• [EN] NOVEL PROCESS FOR THE PREPARATION OF PASIREOTIDE<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION DE PASIRÉOTIDE
  申请人：BIOPHORE INDIA PHARMACEUTICALS PVT LTD

  公开号：WO2016207912A1

  公开（公告）日：2016-12-29

  The present invention relates to a novel process for the preparation of Pasireotide of formula 11 [Cyclo [Phe-4-(OCO-NH-CH2-CH2-NH2)) Pro}-Phg-DTrp-Lys-Tyr(Bzl)]]. The invention also relates to a novel intermediate compound of formula 8 and process thereof which is used for preparation of compound of formula 11.

  本发明涉及一种用于制备化学式11的帕西瑞肽的新型工艺。该发明还涉及一种化学式8的新型中间化合物及其制备工艺，该中间化合物用于制备化合物11。
• Bis 2′-5′-RR-(3′F-A)(3′F-A) cyclic dinucleotide compound and uses thereof
  申请人：ADURO BIOTECH, INC.

  公开号：US10975114B2

  公开（公告）日：2021-04-13

  The present invention provides the cyclic dinucleotide compound 2′2′-RR-(3′F-A)(3′F-A) as a highly active immune stimulator that activates DCs via the cytoplasmic receptor known as STING (Stimulator of Interferon Genes), and compositions and uses thereof.

  本发明提供了环二核苷酸化合物2′2′-RR-(3′F-A)(3′F-A)，作为一种高活性的免疫刺激剂，通过细胞质受体STING（干扰素基因刺激剂）激活DCs，以及其组合物和用途。
• SOMATOSTATIN ANALOGUES
  申请人：Albert Rainer

  公开号：US20090069225A1

  公开（公告）日：2009-03-12

  The invention provides cyclo[4-(NH 2 —C 2 H 4 —NH—CO—O—)Pro}-Phg-DTrp-Lys-Tyr(4-Benzyl)-Phe], optionally in protected form, or a pharmaceutically acceptable salt or complex thereof, which has interesting pharmaceutical properties.

  该发明提供了cyclo[4-(NH2—C2H4—NH—CO—O—)Pro}-Phg-DTrp-Lys-Tyr(4-Benzyl)-Phe]，可选择以保护形式出现，或其药物学上可接受的盐或络合物，具有有趣的药物学特性。
• ROBUST CONTROLLED-RELEASE PEPTIDE FORMULATIONS
  申请人：CAMURUS AB

  公开号：US20140329749A1

  公开（公告）日：2014-11-06

  The present invention relates to compositions forming a low viscosity mixture of: a. 25-55 wt. % of at least one diacyl glycerol and/or at least one tocopherol; b. 25-55 wt. % of at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations over two carbon chains; c. 5-25 wt. % of at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein 0.1-10 wt. % of at least one peptide active agent comprising at least one somatostatin receptor agonist is dissolved or dispersed in the low viscosity mixture; and wherein the pre-formulation forms, or is capable of forming, at least one non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, and to pre-filled administration devices and kits containing the formulations.

  本发明涉及一种组合物，形成低粘度混合物，包括：a.25-55重量％的至少一种二酰基甘油和/或至少一种生育酚；b.25-55重量％的至少一种磷脂组分，包括具有i. 极性头基团，其中包含超过50％的磷脂酰乙醇胺，并且ii. 两个酰基链，每个酰基链独立地具有16到20个碳，其中至少一个酰基链在碳链中具有至少一个不饱和度，并且在两个碳链上没有超过四个不饱和度；c.5-25重量％的至少一种生物相容的含氧低粘度有机溶剂；其中0.1-10重量％的至少一种肽活性剂包括至少一种生长抑素受体激动剂溶解或分散在低粘度混合物中；并且预制剂在与水性液体接触时形成至少一种非层状液晶相结构。本发明还涉及包括这种配方的治疗方法，以及预填充的给药装置和套件。
• ROBUST CONTROLLED-RELEASE FORMULATIONS
  申请人：CAMURUS AB

  公开号：US20140348903A1

  公开（公告）日：2014-11-27

  The present invention relates to compositions forming a low viscosity mixture of: a. at least one diacyl glycerol and/or at least one tocopherol; b. at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each independently having 16 to 20 carbons wherein at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations over two carbon chains; c. at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein optionally at least one bioactive agent is dissolved or dispersed in the low viscosity mixture; and wherein the pre-formulation forms, or is capable of forming, at least one non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, and to pre-filled administration devices and kits containing the formulations.

  本发明涉及构成低粘度混合物的组合物，包括：a. 至少一种二酰基甘油和/或至少一种生育酚；b. 至少一种磷脂成分，包括具有i. 极性头基含有50％以上磷脂酰乙醇胺，和ii. 两个脂肪酰链，每个链独立具有16到20个碳，其中至少一个脂肪酰链在碳链中具有至少一个不饱和度，并且两个碳链上不超过四个不饱和度；c. 至少一种生物相容的含氧低粘度有机溶剂；其中可选地，至少一种生物活性剂溶解或分散在低粘度混合物中；并且预制剂在与水性流体接触时形成，或能够形成至少一个非层状液晶相结构。本发明还涉及包括这些配方的治疗方法，以及预装的给药装置和工具包。