依维莫司 | 159351-69-6

• 物质功能分类: 原料药 - 影响免疫功能药 - 免疫抑制药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 中文名称: 依维莫司
• 中文别名: 42-O-(2-羟乙基)纳巴霉素；42-O-(2-羟乙基)雷帕霉素；依维菌素
• 英文名称: everolimus
• 英文别名: RAD001；(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone；afinitor；Certican；42-O-(2-hydroxyethyl)rapamycin；(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(15,3R,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；40-O-(2-hydroxyethyl)rapamycin；(1R,9S,12S,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
• CAS: 159351-69-6
• 化学式: C₅₃H₈₃NO₁₄
• 分子量: 958.24
• InChiKey: HKVAMNSJSFKALM-GKUWKFKPSA-N

物化性质

• 熔点：
  NA
• 沸点：
  998.7±75.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  可溶于DMSO（高达100mg/ml）或乙醇（高达100mg/ml）。
• 稳定性/保质期：

  Stable under recommended storage conditions.

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（磷糖酸磷脂酶）的底物。在人体血液中检测到的依维莫司的6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磷脂酰胆碱共轭物。在体外，依维莫司竞争性抑制CYP3A4的代谢，并且是CYP2D6底物右美沙芬的混合抑制剂。

Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.

来源:DrugBank

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轭物。这些代谢物也在毒性研究中使用的动物物种中被识别，并且活性大约比依维莫司本身低100倍。

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)

代谢

依维莫司已知的人类代谢物包括 (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-二羟基-12-[(2R)-1-[(1S,3R,4R)-4-羟基-3-甲氧基环己基]丙烷-2-基]-19,30-二甲氧基-15,17,21,23,29,35-六甲基-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十八烷-16,24,26,28-四烯-2,3,10,14,20-五酮 和 (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24E,30S,32S,35R)-1,18-二羟基-12-[(2R)-1-[(1S,3R,4R)-3-羟基-4-(2-羟基乙氧基)环己基]丙烷-2-基]-19,30-二甲氧基-15,17,21,23,29,35-六甲基-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十八烷-16,24,26,28-四烯-2,3,10,14,20-五酮。

Everolimus has known human metabolites that include (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-Dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-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 and (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-3-hydroxy-4-(2-hydroxyethoxy)cyclohexyl]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.

来源:NORMAN Suspect List Exchange

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-中等免疫风险的器官排斥的预防。它还用于成人肝移植患者中异体移植物排斥的预防。人类暴露和毒性：人类对过量的依维莫司的经验非常有限。有一例2岁儿童意外摄入1.5 mg依维莫司的情况，未观察到不良反应。单次剂量高达25 mg已给予移植患者，急性耐受性可接受。在没有环孢素的情况下，单次剂量高达70 mg已给予，急性耐受性可接受。依维莫司具有免疫抑制作用，可能会使患者易患细菌、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。也有报道依维莫司引起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，其中一些是致命的。动物研究：依维莫司在为期2年的小鼠和大鼠口服灌胃给药研究中未显示致癌性，剂量为0.9 mg/kg。在动物生殖研究中，雌性大鼠在交配前和通过器官形成期口服给予依维莫司，引起了胚胎-胎儿毒性，包括增加吸收、着床前和着床后丢失、活胎数量减少、畸形（例如，胸骨裂）和骨骼发育迟缓。这些效应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 mg/kg（0.6 mg/平方米）的情况下。在兔中，以0.8 mg/kg（9.6 mg/平方米）的口服剂量发生的胚毒性表现为吸收增加，这种效应在兔中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给药。在0.1 mg/kg（0.6 mg/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）有所降低。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，在0.5 mg/kg及以上剂量的睾丸形态受到影响，在5 mg/kg时精子活力、精子头数和血浆睾酮浓度降低，导致雄性生育能力下降。在给药后13周检查的动物中，这些发现的可逆性有证据。在大鼠中，0.5 mg/kg的剂量导致AUC在临床暴露范围内，而5 mg/kg的剂量导致AUC大约是人类接受0.75 mg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。依维莫司在细菌逆转突变、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中或在小鼠微核试验中每天两次剂量为500 mg/kg的体内试验中均未显示致突变性。

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

• 肝毒性

血清酶升高发生在多达四分之一的服用依维莫司的患者中，但异常通常是轻微的、无症状的，并且是自限性的，很少需要调整剂量或停药。肝功能测试升高超过5倍ULN的情况只发生在1%到2%的治疗患者中。相比之下，尽管依维莫司在多种恶性和非恶性综合征中广泛使用，但没有将特异质、临床上明显的急性肝损伤与依维莫司治疗联系起来。血清酶、胆红素升高和肝炎被列为依维莫司产品标签中的潜在不良事件。因此，由于依维莫司引起的伴有黄疸的急性临床上明显的肝损伤可能非常罕见，如果真的发生的话。 重要的是，依维莫司具有免疫抑制作用，癌症患者的治疗与乙型肝炎病毒再激活的发作有关，这可能是严重的，甚至致命的。反向血清转换（在预先存在乙型肝炎抗体的人中发展HBsAg，无论是抗-HBs还是抗-HBc）也已有报道。 可能性评分：E*（未证实的，也不太可能是临床上明显肝损伤的原因，但能够诱导乙型肝炎病毒的再激活）。

Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy despite its wide scale use in several malignant and non-malignant syndromes. Elevations in serum enzymes and bilirubin and hepatitis are listed as potential adverse events in the product label for everolimun. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all. Importantly, everolimus is immunosuppressive and therapy in patients with cancer has been associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has also been reported. Likelihood score: E* (unproven and also unlikely cause of clinically apparent liver injury but capable of inducing reactivation of hepatitis B).

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：在一项患者中，服用依维莫司的母亲初乳中未检测到依维莫司；然而，关于母乳喂养期间使用依维莫司的信息并不充分。可能更倾向于使用其他药物，特别是在哺乳新生儿或早产儿时。 ◉ 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:In one patient, everolimus was not detected in the colostrum of a mother taking everolimus; however, no information is available on the use of everolimus during breastfeeding. An alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ 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

• 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的制造商建议，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血脂药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，单次剂量的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率。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)

吸收、分配和排泄

• 吸收

在患有晚期实体瘤的患者中，口服剂量从5毫克到70毫克，峰值依维莫司浓度在给药后1到2小时达到。在单次剂量后，Cmax在5毫克到10毫克之间呈剂量正比。在20毫克及更高剂量时，Cmax的增加小于剂量正比，然而AUC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，稳态在2周内达到。SEGA（室管膜下巨细胞星形细胞瘤）和TSC（结节性硬化症）患者的剂量正比：在患有SEGA和TSC的患者中，依维莫司的Cmin在大约1.35 mg/m2到14.4 mg/m2的剂量范围内呈剂量正比。

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 between 5 mg and 10 mg. At 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. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在给接受环孢素的移植患者单次给药放射性标记的依维莫司后，大部分（80%）的放射性活性从粪便中回收，只有很少量（5%）通过尿液排出。

After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

依维莫司的血液到血浆比率为17%至73%。

The blood-to-plasma ratio of everolimus is 17% to 73%.

来源:DrugBank

吸收、分配和排泄

• 清除

在给予3毫克放射性标记的依维莫司后，80%的放射性活性从粪便中回收，而5%通过尿液排出。

Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.

来源:DrugBank

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，该比率从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得到的末端相的表观分布体积（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)

安全信息

• 危险品标志：
  T
• 安全说明：
  S45
• 危险类别码：
  R48/25
• WGK Germany：
  2
• 海关编码：
  29349990
• 危险品运输编号：
  UN 1648 3 / PGII
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

西罗莫司衍生物——依维莫司

**依维莫司**是西罗莫司的衍生物，又称40-O-(2-羟乙基)-雷帕霉素或40-O-(2-羟乙基)-西罗莫司。它是一种激酶类药物，属于干扰细胞通讯以防止肿瘤细胞生长的一类口服哺乳动物雷帕霉素(mTOR)抑制剂。临床上主要用于预防肾移植和心脏移植手术后的排斥反应，目前也可用于治疗已使用过舒尼替尼（Sutent, 辉瑞制药）和索拉非尼（Nexavar, 拜耳制药）的晚期肾癌患者，并且其毒副作用相对较轻。

作用机制

依维莫司通过与细胞内蛋白质FKBP12结合，形成抑制性的复合体mTORC1，从而抑制mTOR激酶活性。这种抑制作用会导致转录调节因子S6核糖体蛋白激酶（S6K1）和真核生物延伸因子4E结合蛋白（4E-BP）的活性下降，进而影响细胞增殖并诱导细胞凋亡及自噬。依维莫司还表现出抗血管生成/血管效果，并且在体外与RApamycin相比，具有更强的免疫抑制作用。

临床应用

**依维莫司**于2009年3月30日获得美国FDA批准用于肾癌治疗。研究结果表明，依维莫司可显著延长癌症病人的无进展生存期，并为经舒尼替尼或索拉非尼治疗无效的晚期肾细胞癌病人提供新的治疗选择。2009年8月，欧盟委员会批准诺华生产的Afinitor(依维莫司)片剂用于晚期肾细胞癌(RCC)患者的治疗。

生物活性与靶点

• Everolimus (RAD001, SDZ-RAD)是一种mTOR抑制剂，在无细胞试验中的IC50值为1.6-2.4 nM。
• 该药物作用于FKBP12和mTOR，其在无细胞实验中的IC50分别为1.6 nM-2.4 nM。

体外研究

• Everolimus与RApamycin相比，在抑制免疫活性方面表现更优。它能与固定化的FK 506竞争性结合到生物素化的FKBP12上，IC50为1.6 nM-2.4 nM。
• 在BALB/c和CBA小鼠脾脏细胞中，Everolimus抑制双向MLR的IC50值为0.12 nM-1.8 nM。此外，在VEGF诱导的HUVEC增殖和bFGF诱导的 HUVEC增殖方面，其抗血管生成/血管效果明显，IC50分别为0.12 nM和 0.8 nM。
• 最新研究显示Everolimus可抑制BT474 细胞系和原发性乳腺癌细胞的全部细胞和干细胞生长。当作用于原发性乳腺癌时，IC50为 156 nM；在BT474细胞中，该值降低至71 nM。

体内研究

• Everolimus (0.1 到 10 mg/kg)能够抑制B16/BL6黑色素瘤的原代生长和淋巴结转移，并且这种作用具有剂量依赖性。
• 在携带BT474干细胞移植瘤动物模型中，Everolimus能显著降低肿瘤体积。

以上信息展示了依维莫司在多个方面的生物学特性和临床应用潜力。随着研究的深入，更多关于其机制与效果的研究将继续推进这一药物的发展。通过不断优化和探索，有望为更多患者带来更有效的治疗选择。

Target	Value
FKBP12 (Cell-free assay)	1.6-2.4 nM
mTOR (FKBP12) (Cell-free assay)	1.6 nM-2.4 nM

反应信息

• 作为反应物：
  描述：

  依维莫司 在 氟化氢吡啶 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 21.0h， 生成 (22E,24E,26E,27E,35R,36S,37R,38R,40S,42S,44S,45S,46R,47R,56R)-46,56-dihydroxy-45-[(1R)-2-[(1S,3R,4R)-4-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-3-methoxy-cyclohexyl]-1-methyl-ethyl]-44,47-dimethoxy-35,36,37,38,48,49-hexamethyl-66,67-dioxa-57-azatricyclohexatriaconta-22,24,26(48),27(49)-tetraene-50,51,52,53,54-pentone
  参考文献：
  名称：

  WO2019241789A5

  摘要：

  公开号：

  WO2019241789A5
• 作为产物：
  描述：

  雷帕霉素 在 2,6-二甲基吡啶 、 盐酸 、 三氟甲磺酸酐 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 1.5h， 生成 依维莫司
  参考文献：
  名称：

  [EN] PROCESS FOR THE SYNTHESIS OF EVEROLIMUS AND INTERMEDIATES THEREOF
  [FR] PROCÉDÉ DE SYNTHÈSE D'ÉVÉROLIMUS ET D'INTERMÉDIAIRES DE CE DERNIER

  摘要：

  这项发明涉及一种用于合成化学式（I）的依维莫司和其中间体的新工艺。

  公开号：

  WO2016020664A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
  申请人：Wang Zhong

  公开号：US20120077814A1

  公开（公告）日：2012-03-29

  The disclosure provides biologically active compounds of formula (I): and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.

  该披露提供了化学式(I)的生物活性化合物及其药用盐，含有这些化合物的组合物，以及在各种应用中使用这些化合物的方法，例如用于治疗与E1型激活酶相关的疾病或紊乱，特别是与Nedd8激活酶(NAE)相关的疾病或紊乱。
• [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] SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION<br/>[FR] COMPOSÉS DE BENZYLAMINE SUBSTITUÉS, LEUR UTILISATION EN MÉDECINE, EN PARTICULIER DANS LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE C (VHC)
  申请人：ASTEX THERAPEUTICS LTD

  公开号：WO2013064538A1

  公开（公告）日：2013-05-10

  The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R0 is hydrogen or C1-2 alkyl; R1a is selected from CONH2; CO2H; an optionally substituted acyclic C1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R2 is selected from hydrogen and a group R2a; R2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R1 and R2 is other than hydrogen; R3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R4a is selected from halogen; cyano; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C1-4 alkyl; and C1-2 alkoxy-C1-4 alkyl; R5 is selected from hydrogen and a substituent R5a; and R5a is selected from C1-2 alkyl optionally substituted with one or more fluorine atoms; C1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.

  该发明提供了以下式（I）的化合物，或其盐、N-氧化物或互变异构体，其中A为CH、CF或氮；E为CH、CF或氮；R0为氢或C1-2烷基；R1a选自CONH2；CO2H；一个可选择取代的非环状C1-8碳氢化合物基团；以及一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1、2、3或4个是从O、N和S中选择的杂原子环成员；R2选自氢和一个基团R2a；R2a选自一个可选择取代的非环状d-8碳氢化合物基团；一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1或2个环成员是从O、N和S中选择的杂原子环成员；以及一个可选择取代的含有9或10个环成员的双环杂环基团，其中1或2个环成员是氮原子；其中R1和R2中至少一个不是氢；R3选自一个可选择取代的含有0、1、2或3个从N、O和S中选择的杂原子环成员的3至10个成员的单环或双环碳环或杂环环；R4a选自卤素；氰基；C1-4烷基，可选择取代一个或多个氟原子；C1-4烷氧基，可选择取代一个或多个氟原子；羟基-C1-4烷基；和C1-2烷氧基-C1-4烷基；R5选自氢和一个取代基R5a；R5a选自C1-2烷基，可选择取代一个或多个氟原子；C1-3烷氧基，可选择取代一个或多个氟原子；卤素；环丙基；氰基；和氨基。这些化合物对丙型肝炎病毒具有活性，并可用于预防或治疗丙型肝炎病毒感染。