摩熵化学
数据库官网
小程序
打开微信扫一扫
首页 分子通 化学资讯 化学百科 反应查询 关于我们
请输入关键词

(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

中文名称
——
中文别名
——
英文名称
(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
英文别名
——
(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone化学式
CAS
——
化学式
C53H83NO14
mdl
——
分子量
958.2
InChiKey
HKVAMNSJSFKALM-XKYNZCQCSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    5.9
  • 重原子数:
    68
  • 可旋转键数:
    9
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.75
  • 拓扑面积:
    205
  • 氢给体数:
    3
  • 氢受体数:
    14

ADMET

代谢
依维莫司是CYP3A4和PgP的底物。口服给药后,依维莫司是人类血液中的主要循环成分。已经在人类血液中检测到依维莫司的六种主要代谢物,包括三种单羟基化代谢物,两种水解开环产物,以及一种依维莫司的磷脂酰胆碱共价结合物。这些代谢物也在毒性研究中使用的动物种类中被识别,并且显示出比依维莫司本身大约低100倍的活动性。
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
识别和使用:依维莫司是一种哺乳动物雷帕霉素靶蛋白(mTOR)激酶的抑制剂,是一种抗肿瘤剂和大环内酯类免疫抑制剂。依维莫司(商品名Afinitor)用于治疗某些类型的乳腺癌、胰腺神经内分泌肿瘤、肾细胞癌、伴有结节性硬化症的肾血管平滑肌脂肪瘤以及伴有结节性硬化症的室管膜下巨细胞星形细胞瘤。依维莫司(商品名Zortress)用于成人肾移植患者中低-中度免疫风险的器官排斥预防。它还用于成人肝移植患者的异体移植物排斥预防。人类暴露和毒性:关于人类过量服用的报道非常有限。有一例2岁儿童意外摄入1.5毫克依维莫司,未观察到不良反应。单次剂量高达25毫克的移植患者已接受治疗,具有可接受的急性耐受性。在没有环孢素的情况下,单次剂量高达70毫克的患者已接受治疗,具有可接受的急性耐受性。依维莫司具有免疫抑制作用,可能使患者易患细菌、真菌、病毒或原虫感染,包括机会性感染。其中一些感染是严重的(例如,导致呼吸或肝衰竭)或致命的。还报告了与依维莫司相关的致命非感染性肺炎。在依维莫司(Afinitor)的临床试验中,已报告血清肌酐浓度升高和蛋白尿。在接受依维莫司治疗的病人中也观察到了肾衰竭(包括急性肾衰竭)的情况,有些是致命的。动物研究:在小鼠和大鼠中,通过口服灌胃每天给药0.9毫克/千克,持续2年,未发现致癌性。在动物生殖研究中,给雌性大鼠在交配前和器官形成期间口服依维莫司,诱发了胚胎-胎儿毒性,包括增加吸收、着床前和着床后损失、活胎儿数量减少、畸形(例如,胸骨裂)和骨骼发育迟缓。这些影响发生在没有母体毒性的情况下。在大鼠中,胚胎-胎儿毒性发生在剂量大于或等于0.1毫克/千克(0.6毫克/平方米)时。在兔中,以0.8毫克/千克(9.6毫克/平方米)的口服剂量发生明显的胚胎毒性,表现为吸收增加。兔中的这种效应发生在母体毒性的存在下。在大鼠的产前和产后发育研究中,动物从着床期到哺乳期接受给药。在0.1毫克/千克(0.6毫克/平方米)的剂量下,对分娩和哺乳或母体毒性迹象没有不良影响;然而,后代体重(与对照组相比减少多达9%)和存活率(大约5%死亡或丢失)有所下降。后代的发展参数(形态发育、运动活动、学习或生育评估)没有药物相关的影响。在大鼠的13周雄性生育口服灌胃研究中,0.5毫克/千克及以上的剂量影响了睾丸形态,5毫克/千克的剂量降低了精子活力、精子头数和血浆睾酮浓度,导致雄性生育能力下降。在给药后13周检查的动物中,这些发现具有可逆性的证据。大鼠的0.5毫克/千克剂量导致AUCs在临床暴露范围内,而5毫克/千克的剂量导致AUCs大约是人类接受0.75毫克每日两次的5倍。依维莫司在非临床研究中未影响雌性生育能力,但依维莫司穿过胎盘并对胎儿有毒。在细菌反向突变、小鼠淋巴瘤胸腺嘧啶激酶试验、使用V79中国仓鼠细胞的染色体畸变试验或小鼠微核试验中,依维莫司每日两次剂量为500毫克/千克的活体试验中,未发现诱变性。
IDENTIFICATION AND USE: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent and macrolide immunosuppressive agent. Everolimus (brand name Afinitor) is used in the treatment of certain types of breast cancers, neuroendocrine tumors of pancreatic origin, renal cell carcinoma, renal angiomyolipoma with tuberous sclerosis complex, and subependymal giant cell astrocytoma with tuberous sclerosis complex. Everolimus (brand name Zortress) is used for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. It is also used for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. HUMAN EXPOSURE AND TOXICITY: Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections. Some of these infections have been severe (e.g., resulting in respiratory or hepatic failure) or fatal. Fatal noninfectious pneumonitis also has been reported with everolimus. Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients. ANIMAL STUDIES: Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses of 0.9 mg/kg. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses greater than or equal to 0.1 mg/kg (0.6 mg/sq m). In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/sq m. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/sq m), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (approximately 5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily. Everolimus did not affect female fertility in nonclinical studies, but everolimus crossed the placenta and was toxic to the conceptus. Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
使用HMG-CoA还原酶抑制剂(如洛伐他汀或辛伐他汀)在肾移植患者中进行的依维莫司与环孢素的临床试验中强烈不推荐,因为HMG-CoA还原酶抑制剂与环孢素之间存在相互作用。Zortress的生产商建议,在接受依维莫司和环孢素治疗的同时正在接受HMG-CoA还原酶抑制剂和/或纤维酸衍生物的患者中,应监测可能发生的横纹肌溶解症和其他不良反应,这些不良反应在这些降脂药物的处方信息中有描述。
Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
在健康个体中进行的研究表明,单剂量依维莫司与阿托伐他汀(CYP3A4底物)或普伐他汀(非CYP3A4底物和P-糖蛋白底物)之间没有临床重要的药代动力学相互作用;血浆中HMG-CoA还原酶的生物活性也没有受到显著影响。因此,当依维莫司与阿托伐他汀或普伐他汀同时使用时,不需要调整剂量。在一项群体药代动力学分析中,辛伐他汀(CYP3A4底物)并未影响依维莫司的清除。Zortress的生产商警告,这些结果不能推广到其他HMG-CoA还原酶抑制剂。
Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
与依维莫司联用血管紧张素转换酶(ACE)抑制剂可能会增加血管性水肿的风险。如果必要的话,应该考虑在依维莫司治疗的患者中使用其他抗高血压药物。
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema. The use of alternative antihypertensive agents should be considered in everolimus-treated patients, if necessary.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
如果在SEGA患者中需要与P-糖蛋白抑制剂联合使用,应将依维莫司的剂量减少约50%,以维持5-10 ng/mL的依维莫司谷浓度。如果在每日接受2.5 mg剂量的患者中需要减少剂量,应考虑隔日给药。随后的给药应根据治疗药物监测个性化调整。在添加P-糖蛋白抑制剂后大约2周,应评估依维莫司的谷浓度。如果停止P-糖蛋白抑制剂,应将依维莫司的剂量恢复到开始P-糖蛋白抑制剂之前的剂量,并在大约2周后重新评估依维莫司的谷浓度。
If coadministration of a P-gp inhibitor is required in patients with SEGA, everolimus dosage should be reduced by approximately 50% to maintain trough everolimus concentrations of 5-10 ng/mL. If dosage reduction is required in patients receiving 2.5 mg daily, alternate-day dosing should be considered. Subsequent dosing should be individualized based on therapeutic drug monitoring. Trough everolimus concentrations should be assessed approximately 2 weeks after the addition of the P-gp inhibitor. If the P-gp inhibitor is discontinued, the everolimus dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor and the trough everolimus concentration should be reassessed approximately 2 weeks later.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
依维莫司的血液到血浆比率取决于浓度,在5 ng/mL到5000 ng/mL的范围内从17%变化到73%。在健康受试者和中度肝功能损害的患者中,血浆蛋白结合率大约为74%。在维持性肾脏移植患者中,单次给药药代动力学研究的终末相表观分布体积(Vz/F)为342至107升(范围128至589升)。
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
依维莫司的血浆浓度比例,在5至5000 ng/mL的浓度范围内呈浓度依赖性,为17%至73%。在癌症患者中,给予阿芬太10 mg/天的血药浓度下,被血浆限制的依维莫司的量大约为20%。在健康受试者和中度肝功能损害的患者中,血浆蛋白结合率大约为74%。
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在给予晚期实体瘤患者阿芬太利片后,口服剂量从5毫克到70毫克,达到依维莫司峰值浓度的时间为1到2小时。在单次给药后,Cmax(最高血药浓度)与每日剂量在5毫克到10毫克之间呈剂量正比。在单次剂量为20毫克及更高时,Cmax的增加小于剂量正比,然而AUC(药时曲线下面积)在5毫克到70毫克的剂量范围内显示剂量正比。在每日一次给药后,稳态血药浓度在2周内达到。
After administration of Afinitor tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
没有针对癌症患者进行特定的消除研究。在给予接受环孢素的病人单次3毫克的放射性标记的依维莫司后,80%的放射性物质从粪便中回收,而5%通过尿液排出。原药在尿液或粪便中未检测到。依维莫司的平均消除半衰期大约为30小时。
No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
来源:Hazardous Substances Data Bank (HSDB)

文献信息

  • HISTONE H2AX (HH2AX) BIOMARKER FOR FTI SENSITIVITY
    申请人:Basso-Porcaro Andrea Dawn
    公开号:US20110009387A1
    公开(公告)日:2011-01-13
    The present invention relates e.g., to methods for predicting cellular sensitivity to farnesyl protein transferase inhibitors, such as lonafarnib; manumycin A; FTI-276; L-744832; BMS-214662; tipifarnib; BMS-316810K. The methods involve determining if malignant cells exhibit increased expression. of phosphorylated histone H2Ax following contact of one or more of said cells with said inhibitor.
    本发明涉及例如,用于预测细胞对法尼酰蛋白转移酶抑制剂(如洛纳法尼布、马努霉素A、FTI-276、L-744832、BMS-214662、替匹法尼布、BMS-316810K)的敏感性的方法。该方法涉及确定恶性细胞是否在与该抑制剂中的一个或多个细胞接触后表现出磷酸化组蛋白H2Ax的表达增加。
  • ANTI-IGF1R
    申请人:Wang Yan
    公开号:US20110014117A1
    公开(公告)日:2011-01-20
    The present invention relates in part to anti-IGF1R antibodies and antigen-binding compositions thereof along with methods of use thereof. For example, methods of treating medical disorders such as cancer are covered.
    本发明部分涉及抗IGF1R抗体及其抗原结合组成物,以及其使用方法。例如,涵盖了治疗癌症等医学疾病的方法。
  • ANTI-MET IN COMBINATION WITH ANTI-VEGFR2 ANTIBODIES THERAPY FOR CANCER
    申请人:Eli Lilly and Company
    公开号:US20160369004A1
    公开(公告)日:2016-12-22
    The present invention provides preparation of medicaments for use in treating and methods of treating cancer selected from the group consisting of gastric cancer, HCC, and RCC comprising a C8-H241 Ab, preferably, C8-H241-IgG4, more preferably, emibetuzumab, in combination, as described herein, with an anti-VEGFR2 Ab, preferably, ramucirumab.
  • DYE-STABILIZED NANOPARTICLES AND METHODS OF THEIR MANUFACTURE AND THERAPEUTIC USE
    申请人:Memorial Sloan Kettering Cancer Center
    公开号:US20180021259A1
    公开(公告)日:2018-01-25
    Described herein are nanoparticles which are largely made of (e.g., 90 wt. %) hydrophobic drugs and are stabilized by water soluble dyes. The nanoparticles can range in size from 30 nm to 150 nm and have highly negative surface charge (e.g., −55 mV). These nanoparticles are highly soluble in water, stable for days in PBS buffer and can be easily lyophilzed and reconstituted in water. Using quantitative self-assembly prediction calculations, topochemical molecular descriptors were identified and validated as highly predictive indicators of nano-assembly, nanoparticle size, and drug loading. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. The nanoparticles exhibited remarkable anti-tumor efficacy in vitro and in vivo in models of hepatocellular carcinoma.
查看更多

同类化合物

马杜霉素II 雷帕霉素 长川霉素 达福普丁甲磺酸 西罗莫司脂化物 蛎灰菌素A 子囊霉素 威里霉素 唑他莫司 吡美莫司 双氢他克莫司 去甲氧基雷帕霉素 化合物 T32504 化合物 T25424 依维莫司 他克莫司杂质5 他克莫司31-DMT 他克莫司 乌米里莫斯 FK-506一水合物 8-表他克莫司 8,9,14,15,24,25,26,26alpha-八氢-14-羟基-4,12-二甲基-3-(1-甲基乙基)-(3R,4R,5E,10E,12E,14S,26alphaR)-3H-21,18-次氮基-1H,22H-吡咯并[2,1-c][1,8,4,19]二氧杂二氮杂二十四环-1,7,16,22(4H,17H)-四酮 42-O-[2-[[羟基[2-(三甲基铵)乙氧基]亚膦酰基]氧基]乙基]雷帕霉素内盐 42-(二甲基亚膦酰)雷帕霉素 42-(2-四唑基)雷帕霉素 40-O-[2-(叔丁基二甲硅基)氧代]乙基雷帕霉素 37-去亚甲基24,33-二-O-(叔-丁基二甲基硅烷基)-37-氧代-FK-506 31-O-去甲基-Fk506 28-O-甲基-雷帕霉素 24,33-二-O-(叔-丁基二甲基硅烷基)-37,38-去氢-37,38-二羟基-FK-506 24,32-双-O-(tert-butyldimethylsilyl)-他克莫司 22-羟基-33-叔-丁基二甲基硅烷基氧基-异-FK-506 2-甲氧基-5-硝基嘧啶-4-胺 19-表FK-506 15-O-去甲基长川霉素 13-O-去甲基子囊霉素 (E/Z)-FK-50626,28-烯丙酸酯 (2S,5S,6R,10R,11S)-10-庚基-6-羟基-4,11-二甲基-5-(苯基甲基)-2-丙-2-基-1,9-二氧杂-4-氮杂环十二烷-3,8,12-三酮 (1R,2R,4S)-4-{(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-二羟基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五氧代-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十六碳-16,24,26,28-四烯-12-基]丙基}-2-甲氧基环己基2,2,5-三甲基-1,3-二恶烷-5-羧酸酯 (21S)-1-aza-4,4-dimethyl-6,19-dioxa-2,3,7,20-tetraoxobicyclo<19.4.0>pentacosane CCI-779 boronate rapamycin (-)-spongedepsin (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,32SR,35R)-1,18-dihydroxy-30-(3-hydroxypropoxy)-19-methoxy-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-(3-phenylpropoxy)cyclohexyl]-1-methylethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone rapamycin 42-hemiadipate Rapamycin 42-ester with 4-methylpiperazine-1-carboxylic acid rapamycin O-[(S)-2,3-dihydroxypropyloxycarbonyl]rapamycin 29-epirapamycin 40-O-tert-butyldimethylsilyl rapamycin