Antibiotic S 7481F1 | 59865-13-3

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: Antibiotic S 7481F1
• 英文别名: (3R,6S,9S,12S,15S,18R,21S,24S,30R,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• CAS: 59865-13-3
• 化学式: C₆₂H₁₁₁N₁₁O₁₂
• 分子量: 1202.6
• InChiKey: PMATZTZNYRCHOR-VJRYSDSKSA-N

物化性质

• 熔点：
  148-151°C
• 比旋光度：
  D20 -244° (c = 0.6 in chloroform); D20 -189° (c = 0.5 in methanol)
• 沸点：
  838.63°C (rough estimate)
• 密度：
  0.9913 (rough estimate)
• 闪点：
  87℃
• 溶解度：
  乙醇：30 mg/mL
• 物理描述：
  Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)
• 颜色/状态：
  Forms white prismatic crystals from acetone
• 旋光度：
  Optical rotation: -244 degrees @ 20 °C (c = 0.6 in chloroform), - 189 degrees @ 20 °C (c = 0.5 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  12

ADMET

代谢

环孢素在肝脏中通过细胞色素P450 3A（CYP3A）酶系统进行广泛代谢，在一定程度上也会通过胃肠道和肾脏代谢。在人的胆汁、粪便、血液和尿液中已经鉴定出至少25种代谢物。尽管环孢素的环状肽结构对代谢相对抵抗，但侧链被广泛代谢。所有的代谢物与母药相比，生物活性和毒性都降低了。

Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，环孢素治疗的开始与血清胆红素水平的轻度升高有关，通常不伴有血清ALT或碱性磷酸酶的显著增加。血清酶的升高也有描述，但较少见。最近，这些并发症似乎较为罕见，这可能是由于更谨慎的剂量控制和环孢素水平的监测。此外，在治疗没有移植诸多并发症的自身免疫疾病时，环孢素治疗与高达30%的患者出现轻度血清碱性磷酸酶升高有关，但这些异常是无症状的，通常是自限性的，很少需要调整剂量。在几个病例系列中，环孢素治疗也与胆泥和胆石症有关。有临床明显急性肝损伤的孤立病例报告归因于环孢素。发病时间在开始使用环孢素后的几周内，血清酶升高的模式是胆汁淤积。一旦停止使用环孢素，恢复迅速，尚未有因环孢素引起的慢性肝炎或急性肝衰竭的报道。

In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.

来源:LiverTox

毒理性

• 致癌性证据

环孢素A：已知是一种人类致癌物。

Cyclosporin A: known to be a human carcinogen.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

环孢素与许多常用药物有相互作用，必须密切关注药物间相互作用。任何影响微体酶的药物，尤其是CYP3A系统的药物，可能会影响环孢素的血药浓度。抑制这种酶的药物可以减少环孢素的代谢并增加血药浓度。这些包括钙通道阻滞剂（例如，维拉帕米、尼卡地平）、抗真菌药（例如，氟康唑、酮康唑）、抗生素（例如，红霉素）、糖皮质激素（例如，甲基强的松龙）、HIV蛋白酶抑制剂（例如，印地那韦）以及其他药物（例如，别嘌呤醇和甲氧氯普胺）。此外，葡萄柚和葡萄柚汁会阻断CYP3A系统，增加环孢素的血药浓度，因此接受该药物的患者应避免食用。相比之下，诱导CYP3A活性的药物可以增加环孢素的代谢并降低血药浓度。可以通过这种方式降低环孢素浓度的药物包括抗生素（例如，萘夫西林和利福平）、抗惊厥药（例如，苯巴比妥、苯妥英）以及其他药物（例如，奥曲肽、替格瑞洛）。通常，当使用此类组合时，需要密切监测环孢素的血药水平和其他药物的水平。环孢素与西罗莫司之间的相互作用导致建议将两种药物的给药时间分开。西罗莫司会加重环孢素引起的肾功能不全，而环孢素会增加西罗莫司引起的高脂血症和骨髓抑制。其他值得关注的环孢素药物相互作用包括与非甾体抗炎药和其他导致肾功能障碍的药物联合使用时引起的肾毒性增加；当两种药物联合使用时，甲氨蝶呤水平升高；以及包括泼尼松龙、地高辛和洛伐他汀在内的其他药物清除率降低。

Cyclosporine interacts with a wide variety of commonly used drugs, & close attention must be paid to drug interactions. Any drug that affects microsomal enzymes, especially the CYP3A system, may affect cyclosporine blood concns. Substances that inhibit this enzyme can decr cyclosporine metab & incr blood concns. These include calcium channel blockers (e.g., verapamil, nicardipine), antifungal agents (e.g., fluconazole, ketoconazole), antibiotics (e.g., erythromycin), glucocorticoids (e.g., methylprednisolone), HIV-protease inhibitors (e.g., indinavir), & other drugs (e.g., allupurinol & metoclopramide). In addition, grapefruit & grapefruit juice block the CYP3A system & incr cyclosporine blood concns & thus should be avoided by patients receiving the drug. In contrast, drugs that induce CYP3A activity can incr cyclosporine metab & decr blood concns. Drugs that can decr cyclosporine concns in this manner include antibiotics (e.g., nafcillin & refampin), anticonvulsants (e.g., phenobarbital, phenytoin), & other drugs (e.g., octreotide, ticlopidine). In general, close monitoring of cyclosporine blood levels & the levels of other drugs is required when such combinations are used. Interactions between cyclosporine & sirolimus have led to the recommendation that admin of the two drugs be separated by time. Sirolimus aggravate cyclosporine-induced renal dysfunction, while cyclosporine increases sirolimus-induced hyperlipemia & myelosuppression. Other cyclosporine-drug interactions of concern include additive nephrotoxicity when coadministered with nonsteroidal antiinflammatory drugs & other drugs that cause renal dysfunction; elevation in methotrexate levels when the two drugs are coadministered; & reduced clearance of other drugs, including prednisolone, digoxin, & lovastatin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

环孢素增加地高辛的分布体积、半衰期和肾消除分数。环孢素增强维库溴铵的阻断作用并延长恢复时间。已经临床确认对环孢素代谢有影响的药物包括：钙通道阻滞剂、地尔硫卓、硝苯地平、维拉帕米、头孢曲松、红霉素、诺氟沙星、酮康唑、氟康唑、环丙沙星、约沙霉素、甲基睾酮、奥美拉唑、硫茚酸、性激素、皮质类固醇、美托拉宗、乙酰唑胺、酒精、西咪替丁、达那唑、亚胺培南/西司他丁、伊曲康唑、口服避孕药、普瑞司他菌素-增加血液中环孢素水平；磺胺嘧啶、苯妥英、苯巴比妥、普里米酮、卡马西平、利福平、乙胺丁醇、异烟肼、奎宁、灰黄霉素、利福霉素、华法林、苯丁酸氮芥-降低血液中环孢素水平。/来自表格/

Cyclosporine increases the volume of distribution, half-life, & renally eliminated fraction of digoxin. Cyclosporine potentiates vecuronium blockade & prolongs recovery time. Drugs with clinically established effects on cyclosporine metab are/: calcium channel blockers, Diltiazepam, Nifedipine, Verapamil, Ceftriaxone, Erythromycin, Norfloxacin, Ketoconazole, Fluconazole, Ciprofloxacin, Josamycin, Methyltestosterone, Omeprazole, Sulindac, Sex hormones, Corticosteroids, Metolazone, Acetazolamide, Alcohol, Cimetidine, Danazol, Imipenem/cilastin, Itraconazole, Oral contraceptives, Pristinamycin- Incr blood cyclosporine levels; Sulfadimidine, Phenytoin, Phenobarbital, Primidone, Carbamazepine, Rifampin, Ethambutol, Isoniazid, Quinine, Griseofulvin, Rifamycin, Warfarin, Chlorambucil- Decr blood cyclosporine levels/. /From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与别嘌醇、雄激素、溴隐亭、西咪替丁、克拉霉素、达那唑、地尔硫卓、红霉素、雌激素、氟康唑、HIV蛋白酶抑制剂、伊曲康唑、酮康唑、甲氧氯普胺、咪康唑、奈法唑酮、尼卡地平、维拉帕米合用时，可能会通过抑制细胞色素P450 3A酶而增加环孢素的血药浓度，并可能增加肝毒性和肾毒性的风险；由于咪康唑与酮康唑相似，可以预期它会产生相同的效果；尽管HIV蛋白酶抑制剂和环孢素的联合使用尚未进行研究，但已知HIV蛋白酶抑制剂会抑制细胞色素P450 3A酶；如果这些药物与环孢素同时使用，可能需要频繁监测血液中环孢素的浓度以及肝脏和肾脏功能。

/Concurrent use with allopurinol, androgens, bromocriptine, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, estrogens, fluconazole, HIV protease inhibitors, itraconazole, ketoconazole, metoclopramide, miconazole, nefazodone, nicardipine, verapamil/ may increase blood concentrations of cyclosporine by inhibiting cytochrome p450 3A enzymes, and may increase the risk of hepatotoxicity and nephrotoxicity; because of its similarity to ketoconazole, miconazole may be expected to have the same effect; although concurrent use of HIV protease inhibitors and cyclosporine have not been studied, HIV protease inhibitors are known to inhibit cytochrome p450 3A enzymes; frequent monitoring of blood cyclosporine concentrations and hepatic and renal function may be needed if these drugs are used concurrently with cyclosporine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在口服环孢素后，达到最高血药浓度的时间为1.5-2.0小时。与食物同服会延迟并减少吸收。在给药后30分钟内摄入高脂肪和低脂肪餐分别会使曲线下面积（AUC）减少约13%，使最高浓度减少33%。这使得个体化门诊病人的剂量方案变得至关重要。环孢素在血管外分布广泛。在静脉给药后，稳态分布容积在实体器官移植受者中可高达3-5升/千克。仅有0.1%的环孢素以原形从尿液中排出。...环孢素及其代谢物主要通过胆汁进入粪便排出，只有大约6%通过尿液排出。环孢素也通过人乳排出。

Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

环孢素的吸收在口服给药后是不完全的。吸收的程度取决于多个变量，包括个别患者和使用的配方。环孢素从血液中的消除通常是双相的，终末半衰期为5-18小时。在肾脏移植的成年受者中，静脉输注后的清除率大约为5-7毫升/分钟/千克，但结果会因年龄和患者群体而异。例如，心脏移植患者的清除率较慢，而在儿童中较快。在治疗范围内，给药剂量与血浆浓度-时间曲线下面积之间的关系是线性的，但个体间的变异性很大，因此需要个体监测。

... Absorption of cyclosporine is incomplete following oral admin. The extent of absorption depends upon several variables, including the individual patient & formulation used. The elimination of cyclosporine form the blood is generally biphasic, with a terminal half-life of 5-18 hr. After iv infusion, clearance is approx 5-7 ml/min/kg in adult recipients of renal transplants, but results differ by age & patient populations. For example, clearance is slower in cardiac transplant patients & more rapid in children. The relationship between admin dose & the area under the plasma concn-vs-time curve is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

临床医生可以在移植后的前几天通过持续静脉输液给予环孢素，然后通过每天两次的口服剂量，以达到血浆环孢素浓度（通过高效液相色谱法测量）为75-150 ng/ml（相当于通过放射免疫分析法测量的全血环孢素浓度为300-600 ng/ml）。维持大约75-150 ng/ml的血浆谷浓度似乎是安全的；然而，这并不一定保证免受肾毒性的影响。由于环孢素及其代谢物优先分布进入红细胞，血药水平通常高于血浆水平。当通过放射免疫分析法测量的血液环孢素水平为300-600 ng/ml时，脑脊液水平范围为10-50 ng/ml。10岁以下儿童的表观分布体积约为35 l/kg，成人为4.7 l/kg。

Clinicians can administer cyclosporine by continuous iv infusion during the first few days after transplantation, then orally by twice-daily doses, to achieve plasma cyclosporine concns (measured by HPLC) of 75-150 ng/ml (equivalent to whole blood cyclosporine concns of 300-600 ng/ml measured by radioimmunoassay). It appears safe to maintain a trough plasma cyclosporine concn of about 75-150 ng/ml; however, this does not necessarily guarantee safety from nephrotoxicity. Because of preferential distribution of cyclosporine & its metabolites into red blood cells, blood levels are generally higher than plasma levels. When blood cyclosporine levels are 300-600 ng/ml by radioimmunoassay, cerebrospinal fluid levels range from 10-50 ng/ml. The apparent volume of distribution in children under 10 yr of age is about 35 l/kg, & in adults, 4.7 l/kg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服环孢素350毫克的消除半衰期是8.9小时；在服用1400毫克剂量后，半衰期是11.9小时。环孢素的消除主要是通过肝脏代谢形成18-25种代谢物。环孢素的代谢物几乎没有免疫抑制作用。环孢素在肝脏中通过细胞色素P450III氧化酶广泛代谢；然而，神经毒性和可能的肾毒性通常与环孢素代谢物血药水平升高有关。仅有0.1%的剂量以原形排出。

The elimination half-life of an oral cyclosporine dose of 350 mg is 8.9 hr; after a 1400 mg dose, the half-life is 11.9 hr. Elimination occurs predominantly by metab in the liver to form 18-25 metabolites. Metabolites of cyclosporine possess little immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by cytochrome P450IIIA oxidase; however, neurotoxicity & possibly nephrotoxoicity usually correlate with raised blood levels of cyclosporine metabolites. Only 0.1% of a dose ix s excreted unchanged.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S24/25,S36/37,S45,S53
• 危险类别码：
  R60,R22,R45
• WGK Germany：
  3
• 海关编码：
  2941909000
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  GZ4120000

制备方法与用途

根据提供的信息,以下是关于环孢素的主要内容总结:

化学性质:

• 白色针状结晶
• 溶于甲醇、乙醇、丙酮或乙醚,微溶于水
• [α]D20 -244°(C=0.6，氯仿)
• 急性毒性LD50: 小鼠107mg/kg, 大鼠2329mg/kg, 兔子>1000mg/kg

用途:

• 新型免疫抑制剂
• 抑制T细胞受体信号传导路径,用于分子生物学研究
• 临床用于肾移植、肝肺移植等器官移植
• 治疗自身免疫性疾病
• 对白血病、癌症、结核病有一定疗效
• 具有抗炎作用

副作用:

• 肾毒性:蛋白尿、管型尿等
• 肝毒性:高胆红素血症等
• 神经系统症状:小脑共济失调、感觉异常等
• 消化道反应:恶心呕吐等

生产方法: 以多孢木霉菌为生产菌株,经过发酵提取粗品,再纯化得到环孢素和环孢菌素C组分。

总结来说,环孢素是一种重要的免疫抑制剂,广泛应用于临床器官移植及自身免疫病治疗,但需要注意其潜在的毒副作用。

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 Antibiotic S 7481F1 在 4-二甲氨基吡啶 作用下， 以 甲基叔丁基醚 为溶剂， 以88 %的产率得到acetyl cyclosporine
  参考文献：
  名称：

  WO2024157186A1

  摘要：

  公开号：

文献信息

• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [EN] PYRIMIDINE JAK INHIBITORS FOR THE TREATMENT OF SKIN DISEASES<br/>[FR] INHIBITEURS DE JAK À BASE DE PYRIMIDINE POUR LE TRAITEMENT DE MALADIES DE LA PEAU
  申请人：THERAVANCE BIOPHARMA R&D IP LLC

  公开号：WO2020219640A1

  公开（公告）日：2020-10-29

  The invention provides compounds of formula (I): or pharmaceutically-acceptable salts thereof, that are inhibitors of Janus kinases. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune skin diseases.

  该发明提供了式(I)的化合物或其药用可接受盐，这些化合物是Janus激酶的抑制剂。该发明还提供了包含这些化合物的药物组合物，以及使用这些化合物治疗炎症性和自身免疫性皮肤疾病的方法。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。