钆8,11-二(羧酸甲基)-14-{2-[(2-甲氧基乙基)氨基]-2-氧代乙基}-6-氧代-2-氧杂-5,8,11,14-四氮杂十六烷-16-酸酯 | 131069-91-5

• 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: 钆8,11-二(羧酸甲基)-14-{2-[(2-甲氧基乙基)氨基]-2-氧代乙基}-6-氧代-2-氧杂-5,8,11,14-四氮杂十六烷-16-酸酯
• 英文名称: Gadoversetamide
• 英文别名: Gd(N,N''-bis(2-methoxyethylamide-carbamoylmethyl)diethylenetriamine-N,N',N''-triacetate)；gadoversetamide；2-[bis[2-[carboxymethyl-[2-(2-methoxyethylimino)-2-oxidoethyl]amino]ethyl]amino]acetate;gadolinium(3+)
• CAS: 131069-91-5
• 化学式: C₂₀H₃₄N₅O₁₀*Gd
• 分子量: 661.767
• InChiKey: HBEAOBRDTOXWRZ-UHFFFAOYSA-K

物化性质

• 密度：
  d25 1.160
• 溶解度：
  Freely soluble in water
• 粘度：
  3.1 cP at 20 °C; 2.0 cP at 37 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -7.33
• 重原子数：
  36
• 可旋转键数：
  19
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  207
• 氢给体数：
  2
• 氢受体数：
  13

ADMET

代谢

None detected

来源:DrugBank

代谢

Gadoversetamide 不被代谢。

Gadoversetamide is not metabolized.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：钆酸维塞酰胺溶于水。它在医疗应用中作为磁共振成像（MRI）的对比剂使用。 人体暴露和毒性：钆基对比剂会增加急性或慢性严重肾衰竭患者以及由于肝肾综合征或围手术期肝移植期间任何严重程度的急性肾衰竭患者患肾源性系统性纤维化（NSF）的风险。在这些患者中，除非诊断信息是关键的且无法通过非对比增强MRI获得，否则应避免使用钆基对比剂。对于接受血液透析的患者，医生可以考虑在给予钆基对比剂后立即开始血液透析，以增强对比剂的消除。血液透析在预防NSF方面的有效性尚不清楚。可能增加NSF风险的因素包括重复使用或超过推荐剂量的钆基对比剂，以及暴露时肾功能损害的程度。始终应考虑可能的反应，包括严重的、威胁生命的、致命的、过敏性或心血管反应或其他特异质反应，特别是在那些有已知临床超敏反应、哮喘史或其他呼吸系统疾病的患者中。钆的药代动力学受到肾功能损害的影响：随着肾功能下降，曲线下面积、半衰期和稳态分布体积显著增加，而总清除率降低。 动物研究：对标准浓度的钆喷酸葡胺（Magnevist）、钆特醇（ProHance）、钆二胺（Omniscan）和钆酸维塞酰胺进行了评估，并与对照组（生理盐水）和传统的离子型放射性对比剂甲葡胺二酸三钠（Renografin 60）进行了比较。每只小鼠在后肢注射了对比剂或盐水。在四种MR对比剂中，钆喷酸葡胺引起了最大的组织损伤，而钆特醇和钆二胺这两种最低渗透压的对比剂引起的损伤最小。在炎症和坏死方面，钆特醇和钆二胺与钆喷酸葡胺相比，差异具有统计学意义。在对照实验中，对于所有三个变量（坏死、水肿和炎症），钆特醇或钆二胺的结果与盐水没有统计学上的显著差异。钆酸维塞酰胺的渗透压在离子型对比剂（钆喷酸葡胺）和其他两种非离子型对比剂之间，引起的反应与钆喷酸葡胺在坏死和水肿方面无法区分。只有在炎症评分方面，钆酸维塞酰胺与钆喷酸葡胺相比效果较差，具有统计学意义。钆螯合物因渗出导致的组织损伤风险并未被广泛认识。在注射对比剂时，应小心谨慎，避免意外渗出及其有害后果，特别是对于两种较高渗透压的对比剂（钆喷酸葡胺和钆酸维塞酰胺）。麻醉的比格犬被植入仪器以记录心电图和测量动脉血压。每只动物注射了钆酸维塞酰胺、钆喷酸葡胺、钆二胺和钆特醇。钆酸维塞酰胺的静脉注射导致心率和血压短暂下降。注射速率并不影响心率或血压变化的大小。钆酸维塞酰胺、钆喷酸葡胺和钆二胺引起了相似的心血管功能变化。钆特醇的注射引起了相似程度的低血压，但变化持续时间更长。在大鼠中，钆酸维塞酰胺对生育力、生殖性能和出生后胎儿发育没有影响。在大鼠和兔中没有观察到致畸性。钆酸维塞酰胺对雄性大鼠的生育力有负面影响，导致精子细胞减少和退化，当以高于人类剂量四倍（基于体表面积）的剂量连续静脉注射七周时。在连续静脉注射28天，以高于人类剂量六倍（基于体表面积）的剂量时，观察到雄性大鼠生殖器官重量减轻、睾丸生精上皮退化、精子细胞在附睾中存在和精子计数减少。以1至25倍人类剂量（基于体表面积）的剂量对雄性大鼠的生殖系统没有产生不良影响。钆酸维塞酰胺在沙门氏菌typhimurium（Ames试验）、小鼠淋巴瘤突变试验或哺乳动物微核试验中未发现具有诱变性。在无代谢激活的体外CHO染色体畸变试验中呈阳性。尚未进行长期动物研究以评估钆酸维塞酰胺的致癌潜力。

IDENTIFICATION AND USE: Gadoversetamide is soluble in water. It is used as a MRI contrast agent in medical applications. HUMAN EXPOSURE AND TOXICITY: Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency, and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. The possibility of a reaction, including serious, life threatening, fatal, anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered, especially in those patients with a known clinical hypersensitivity, a history of asthma, or other respiratory disorders. Gadolinium pharmacokinetics were affected by renal impairment: area under the curve, half-life, and steady-state distribution volume significantly increased with declining renal function, while total body clearance decreased. ANIMAL STUDIES: Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide were evaluated at standard concentration and compared with a control (physiologic saline) and the conventional ionic radiographic contrast medium meglumine diatrizoate (Renografin 60). Each mouse received a sc injection in the hindlimb of contrast or saline. Of the four MR contrast agents, gadopentetate dimeglumine caused the greatest tissue damage, and gadoteridol and gadodiamide-the two lowest osmolar agents-the least. The difference was statistically significant in terms of both inflammation and necrosis for gadoteridol, and for gadodiamide, when these agents were compared with gadopentetate dimeglumine. In regard to the control experiments, for all three variables (necrosis, edema, and inflammation), there was no statistically significant difference between the results with gadoteridol or gadodiamide and those with saline. Gadoversetamide, which has an osmolality between the ionic agent (gadopentetate dimeglumine) and the other two nonionic agents, caused a reaction that could not be differentiated from that seen with gadopentetate dimeglumine for both necrosis and edema. Only in the scoring of inflammation was the effect less using gadoversetamide compared to gadopentetate dimeglumine with any statistical significance . The risk of tissue damage due to extravasation is not widely appreciated for the gadolinium chelates. Care should be exercised during contrast injection, to avoid inadvertent extravasation and its deleterious consequences, in particular with the two higher osmolar agents (gadopentetate dimeglumine and gadoversetamide). Anesthetized beagles were instrumented to record the electrocardiogram and to measure arterial blood pressure. Each animal was injected with gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoteridol. IV administration of gadoversetamide caused transient decreases in both heart rate and blood pressure. The rate of injection did not affect the magnitude of the heart rate or blood pressure changes. Administration of gadoversetamide, gadopentetate dimeglumine, and gadodiamide elicited equivalent changes in cardiovascular function. Injection of gadoteridol caused a similar degree of hypotension, but the changes lasted longer. Fertility, reproductive performance, and postnatal fetal development were not affected in the rat. No teratogenicity was observed in the rat and in the rabbit. Gadoversetamide had a negative impact on male rat fertility, causing reduction and degeneration of spermatocytes, when given intravenously (four times the human dose based on body surface area (BSA) for seven weeks). Reduction of male rat reproductive organ weight, testicular germinal epithelium degeneration, germ cell presence in epididymides, and reduced sperm count were all seen at intravenous dose (six times the human dose based on BSA) given for 28 days. 1 to 25 times the human dose based on( BSA) doses did not produce adverse effects on the reproductive system in male rats. Gadoversetamide was not found to be mutagenic in the Salmonella typhimurium ( Ames assay), mouse lymphoma mutagenesis assay, or mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive. Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoversetamide.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物：加多司他胺

Compound:gadoversetamide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

在72小时时，肾功能受损患者的平均累积尿排泄率大约为93.5%，而肾功能正常者的平均累积尿排泄率为95.8%。

The mean cumulative urinary excretion of gadoversetamide at 72 hours was approximately 93.5% for renal impaired patients and 95.8% for subjects with normal renal function

来源:DrugBank

吸收、分配和排泄

• 分布容积

162 ± 25 毫升/千克 [正常受试者]

162 ± 25 mL/kg [normal subjects]

来源:DrugBank

吸收、分配和排泄

• 清除

72 ± 16.3 毫升/小时/千克 [健康]

72 +/- 16.3 mL/hr/kg [healthy]

来源:DrugBank

吸收、分配和排泄

Gadoversetamide (0.1 mmol/kg) 主要通过尿液排出，24小时内排出的给药剂量为95.5 ± 17.4%（平均值 ± 标准差）。动物数据显示，标记有153Gd的Gadoversetamide通过粪便排出的量微不足道。在大鼠实验性诱导的无尿症中，肝胆排泄并未显著补偿尿液排出的缺失。正常受试者的Gadoversetamide的肾清除率和血浆清除率相似（分别为69 ± 15.4和72 ± 16.3 mL/hr/kg），表明该药物通过肾小球滤过在肾脏中被清除。在研究的剂量范围内（0.1至0.7 mmol/kg），Gadoversetamide的动力学表现为线性。

Gadoversetamide (0.1 mmol/kg) is eliminated primarily in the urine with 95.5 + or - 17.4% (mean + or - SD) of the administered dose eliminated by 24 hours. Animal data demonstrated that insignificant levels of 153Gd-labeled gadoversetamide are eliminated via the feces. In experimentally induced anephria in the rat, hepatobiliary excretion did not significantly compensate for the absence of urinary elimination. The renal and plasma clearance rates of gadoversetamide in normal subjects are similar (69 + or - 15.4 and 72 + or - 16.3 mL/hr/kg, respectively) indicating that the drug is cleared through the kidneys via glomerular filtration. Within the studied dose range (0.1 to 0.7 mmol/kg), the kinetics of gadoversetamide appear to be linear.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

稳态下，正常受试者中 gadoversetamide 的分布体积为 162 ± 25 毫升/千克，大致相当于细胞外水分的量。

The volume of distribution at steady state of gadoversetamide in normal subjects is 162 + or - 25 mL/kg, roughly equivalent to that of extracellular water.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  氢化铕 、 钆8,11-二(羧酸甲基)-14-{2-[(2-甲氧基乙基)氨基]-2-氧代乙基}-6-氧代-2-氧杂-5,8,11,14-四氮杂十六烷-16-酸酯 以 水 为溶剂， 生成 Eu(N,N''-bis(2-methoxyethylamide-carbamoylmethyl)diethylenetriamine-N,N',N''-triacetate)
  参考文献：
  名称：

  The kinetics of exchange between a lanthanide ion and the gadolinium complex of N,N″-bis(2-methoxyethylamide-carbamoylmethyl)-diethylenetriamine-N,N′,N″-triacetate

  摘要：

  The exchange kinetics of Gd(DTPA-BMEA) with the radioactive tracer Eu(III) have been studied in aqueous solution of 0.15 M ionic strength and 25 degrees C. The exchange is a first-order reaction with the rate expression containing both acid-dependent and acid-independent terms. At pH > 6, the exchange is governed by direct reaction of Eu(III) ions with Gd(DTPA-BMEA), while below pH 6, the rate determining step is proton-catalyzed dissociation of the complex with a first-order dependence on [H+]. The relatively slow association and dissociation of the Ln(DTPA-BMEA) complexes can be attributed to steric effects related to the binding of the two methoxyethylamide groups.

  DOI：

  10.1016/s0020-1693(97)05513-8
• 作为产物：
  描述：

  维塞胺 以71的产率得到钆8,11-二(羧酸甲基)-14-{2-[(2-甲氧基乙基)氨基]-2-氧代乙基}-6-氧代-2-氧杂-5,8,11,14-四氮杂十六烷-16-酸酯
  参考文献：
  名称：

  [EN] NOVEL MAGNETIC RESONANCE IMAGING AGENTS

  摘要：

  (中)新型磁共振成像剂包括与双乙烯三胺五乙酸酰基衍生物（“DTPA”）或乙二胺四乙酸酰基衍生物（“EDTA”）的烷氧基烷基酰胺络合物。这些新型成像剂具有优异的核磁共振成像对比性能和在生理溶液中的高溶解度。一种新型的核磁共振诊断方法涉及向恒温动物注射上述的有效量的复合物，然后将恒温动物暴露于核磁共振成像程序，从而成像恒温动物的至少一部分身体。

  公开号：

  WO1990001024A1

文献信息

• [EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
  申请人：BAYER PHARMA AG

  公开号：WO2016174183A1

  公开（公告）日：2016-11-03

  The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

  本申请涉及至少两种组分的新型组合，组分A和组分B：·组分A是根据本文所定义的式(I)的IRAK4抑制化合物，或其对映体、对映异构体、代谢物、盐、溶剂合物或其盐的溶剂合物；·组分B是BTK抑制化合物，或其药学上可接受的盐；以及，可选地，·一种或多种组分C，它们是药用产品；其中上述定义的化合物A和B中的一种或两种可选择地存在于用于治疗和/或预防疾病的制剂中，准备用于同时、分开或顺序给药，用于治疗和/或预防疾病，以及用于生产用于治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症、淋巴瘤、黄斑变性、慢性阻塞性肺病、肿瘤性疾病和牛皮癣。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• [EN] TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER<br/>[FR] PRODUITS RADIOPHARMACEUTIQUES CIBLÉS POUR LE DIAGNOSTIC ET LE TRAITEMENT DU CANCER DE LA PROSTATE
  申请人：BAYER AS

  公开号：WO2021013978A1

  公开（公告）日：2021-01-28

  A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.

  通用式(I)的化合物：其中：n为1、2或3；R1、R2、R3和R4独立地代表OH或Q；Q代表从群组中选择的组织靶向基团，或其立体异构体、水合物、溶剂合物、盐或其混合物，制备所述化合物的方法，用于制备所述化合物的中间化合物，包含所述化合物的药物组合物和组合物，以及用于制造用于治疗或预防疾病的药物组合物的所述化合物的用途，特别是软组织疾病的治疗或预防，作为唯一药剂或与其他活性成分结合使用。
• [EN] TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS<br/>[FR] ADMINISTRATION CIBLÉE D'UN MÉDICAMENT FAISANT APPEL À DES COUPLEURS FONDÉS SUR L'AFFINITÉ
  申请人：INVICTUS ONCOLOGY PVT LTD

  公开号：WO2015148126A1

  公开（公告）日：2015-10-01

  The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.

  当前的发明揭示了包括通过具有与靶向基团亲和力的分子连接到药物的靶向药物传递共轭物。通常，该共轭物包括一个靶向配体和一个感兴趣的分子，例如，一个治疗剂。靶向配体和感兴趣的分子通过一个亲和配体相互连接。该亲和配体进一步以共价或非共价方式连接到药物或治疗剂。药物可以被修改以使其更溶解，并使其在靶点处从连接分子中解离。
• [EN] 2-HETEROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES FOR THE TREATMENT OF CANCER<br/>[FR] 2-HÉTÉROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES POUR LE TRAITEMENT DU CANCER
  申请人：BAYER AG

  公开号：WO2018146010A1

  公开（公告）日：2018-08-16

  The present invention covers 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I), in which X, R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

  本发明涵盖了一般式(I)的2-杂环芳基-3-酮基-2,3-二氢吡啶嗪-4-羧酰胺化合物，其中X、R1、R2、R3、R4和R5如本文所定义，制备所述化合物的方法，用于制备所述化合物的有用中间体化合物，包含所述化合物的药物组合物和组合物，以及利用所述化合物制造用于治疗或预防疾病的药物组合物，特别是癌症或与异常AHR信号传导相关的疾病，或与失调免疫反应或其他与异常AHR信号传导相关的疾病，作为单一药剂或与其他活性成分组合使用。