[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16Z,18R,19R,21R,23S,24Z,26Z,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate | 162635-04-3

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: [(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16Z,18R,19R,21R,23S,24Z,26Z,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
• CAS: 162635-04-3
• 化学式: C₅₆H₈₇NO₁₆
• 分子量: 1030.3
• InChiKey: CBPNZQVSJQDFBE-QWRHTZMXSA-N

物化性质

• 熔点：
  99-101°C
• 沸点：
  1048.4±75.0 °C(Predicted)
• 密度：
  1.21
• 闪点：
  587.8℃
• 溶解度：
  易溶于可溶于氯仿、甲醇。
• 颜色/状态：
  White to off-white powder
• 解离常数：
  No ionizable functional groups

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  73
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  242
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

西罗莫司是替西莫司的活性代谢物，是人类静脉给药后主要的代谢物。其余代谢物在血浆中的放射性不到10%。

Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Temsirolimus 通过水解代谢为西罗莫司，后者是主要的活性代谢物。Temsirolimus 和西罗莫司均通过细胞色素 P-450（CYP）同工酶 3A4 进行代谢。尽管 Temsirolimus 被代谢为西罗莫司，但 Temsirolimus 本身具有抗肿瘤活性，并不被认为是一种前药。

Temsirolimus is metabolized by hydrolysis to sirolimus, the principal active metabolite. Both temsirolimus and sirolimus also are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外代谢替西罗莫司（雷帕霉素-42-[2,2-双(羟甲基)]-丙酸酯），一种抗肿瘤药物，使用人肝微粒体以及重组人细胞色素P450酶，即CYP3A4、1A2、2A6、2C8、2C9、2C19和2E1进行了研究。通过液相色谱（LC）-串联质谱（MS/MS或MS/MS/MS）检测到15种代谢物。CYP3A4被确定为主要负责该化合物代谢的酶。用重组CYP3A4孵化替西罗莫司产生了从人肝微粒体孵化中检测到的多数代谢物，用于大规模制备代谢物。通过硅胶色谱法随后进行半制备反相高效液相色谱，分离和纯化了单个代谢物，用于结构鉴定和生物活性研究。通过正负质谱（MS）和MS/MS光谱方法，将小代谢物（峰1-7）鉴定为羟基化或去甲基化的大环内酯开环替西罗莫司衍生物。由于这些化合物不稳定且仅以微量存在，因此没有进行进一步的研究。六种主要代谢物被鉴定为36-羟基替西罗莫司（M8）、35-羟基替西罗莫司（M9）、开环的11-羟基替西罗莫司（M10和M11）、N-氧化物替西罗莫司（M12）和32-O-去甲基替西罗莫司（M13），使用结合了LC-MS、MS/MS、MS/MS/MS和NMR技术。与母体化合物相比，这些代谢物对LNCaP细胞增殖的活性显著降低。

The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), N- oxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

CYP3A4抑制剂：潜在的药代动力学相互作用（主要活性代谢物西罗莫司的血药浓度增加）。应避免与强效CYP3A4抑制剂同时使用；如果没有替代品，应考虑调整替西罗莫司的剂量。

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with a potent CYP3A4 inhibitors should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

CYP3A4诱导剂：可能存在药代动力学相互作用（降低主要活性代谢物西罗莫司的血药浓度）。应避免与强效CYP3A4诱导剂同时使用；如果没有替代方案，应考虑调整坦西莫司的剂量。

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with potent CYP3A4 inducers should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用血管紧张素转换酶（ACE）抑制剂治疗期间观察到的血管性水肿型反应。建议谨慎使用。

Angioedema-type reactions observed during concomitant therapy with angiotensin-converting enzyme (ACE) inhibitors. Caution is advised.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

接受联合治疗的患者颅内出血风险增加。需谨慎。

Increased risk of intracerebral bleeding in patients receiving concomitant therapy. Caution is advised.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

对于静脉注射的坦西罗利木过量的情况，没有特定的治疗方法。

There is no specific treatment for Temsirolimus intravenous overdose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在癌症患者中单次给予25毫克替西罗利姆后，全血中替西罗利姆的平均Cmax为585 ng/mL（变异系数，CV=14%），血液中的平均AUC为1627 ng·hr/mL（CV=26%）。通常Cmax发生在输注结束时。在1毫克到25毫克的剂量范围内，替西罗利姆的暴露量呈小于剂量比例的方式增加，而西罗利姆的暴露量则与剂量成比例增加。在癌症患者中单次给予25毫克静脉注射后，西罗利姆的AUC是替西罗利姆AUC的2.7倍，这主要是由于西罗利姆的半衰期更长。

Following administration of a single 25 mg dose of temsirolimus in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng.hr/mL (CV=26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予单次25毫克静脉注射后，患有癌症的患者全血中替西罗利姆的稳态分布体积为172升。替西罗利姆和西罗利姆都会广泛地分配到形成的血细胞中。

Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在癌症患者中，单次服用25毫克坦西莫利布斯后，坦西莫利布斯的平均（变异系数）系统清除率为16.2（22%）升/小时。

Following a single 25 mg dose of temsirolimus in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

不知道西罗莫司是否会被分泌到人乳中...

It is not known whether temsirolimus is excreted into human milk...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射单次放射性标记的替西罗莫司剂量后，大约78%的总放射性在14天内通过粪便回收，4.6%通过尿液回收。

Following IV administration of a single radiolabeled dose of temsirolimus, approximately 78% of the total radioactivity is recovered in feces and 4.6% in urine within 14 days.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  29349990

制备方法与用途

概述

替西罗莫司（temsirolimus），又称西罗莫司酯化物，是由辉瑞医药研发的一种靶向性抗肿瘤药物，用于治疗进展性肾癌。它是首个针对肾癌的靶向治疗药物，并且是唯一上市的特异性抑制mTOR激酶的药物。

相关研究

mTOR激酶在调节细胞增殖、生长和存活方面起着重要作用。体外研究表明，替西罗莫司通过抑制mTOR激酶导致血管内皮生长因子（VEGF）水平下降，进而阻止新生血管的发展，最终导致癌细胞死亡。

应用

在我国尚未上市，但国外的临床试验结果显示，替西罗莫司对晚期肾癌有较好的疗效，具有广阔的应用前景。

药理作用

mTOR是一种多功能激酶，属于磷脂酰肌醇3激酶（PI3K）蛋白激酶家族成员。作为PI3K/AKT信号通路的下游效应蛋白，其底物主要控制与细胞生长和增殖密切相关的蛋白质合成。肾透明细胞癌中普遍存在PI3K-AKT-mTOR信号传导通路的过度激活。

制备

1. 坦罗莫司半成品制备：将8.3g粗品（纯度75.68%，西罗莫司3.47%，异构体16.48%）溶解于25mL乙酸乙酯中，上样至正相硅球填料柱进行梯度洗脱。在20℃条件下收集组分，并在30℃下减压浓缩至干，得到纯度为84.78%，西罗莫司0.02%，异构体13.28%的半成品。

2. 进一步精制：通过后续处理，最终获得高纯度的替西罗莫司产品。

体内与体外研究

• 体外研究：替西罗莫司抑制核糖体蛋白S6磷酸化。在PTEN阳性的DU145细胞中比在PTEN阴性的PC-3细胞中更为有效，且能够显著抑制细胞生长和克隆存活，作用呈浓度依赖性。对原代人淋巴细胞性白血病（ALL）细胞的处理也显示了显著抑制增殖并诱导凋亡的效果。

• 体内研究：替西罗莫司以20 mg/kg剂量腹腔注射，每周5天，能够显著延迟DAOY移植瘤生长。在较高剂量（100 mg/kg）下单独给药一周内，肿瘤体积下降37%。处理两周也延缓了对Rapamycin耐受的U251移植瘤生长。此外，在患Huntington疾病的小鼠模型中，替西罗莫司能够抑制mTOR并改善多种行为任务表现。它还能够在皮下诱导显著的抗癌反应，并在携带人ALL的NOD/SCID移植瘤模型中降低外周血膨胀和脾肿大。

这些研究结果表明替西罗莫司具有良好的治疗潜力，特别是在抗肿瘤方面显示出显著效果。