dantrolene | 833480-90-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: dantrolene
• 英文别名: 1-[(E)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione
• CAS: 833480-90-3
• 化学式: C₁₄H₁₀N₄O₅
• 分子量: 314.257
• InChiKey: OZOMQRBLCMDCEG-VIZOYTHASA-N

物化性质

• 物理描述：
  Crystals (in aqueous DMF). (NTP, 1992)
• 颜色/状态：
  CRYSTALS FROM AQ DIMETHYLFORMAMIDE
• 熔点：
  279-280 °C
• 溶解度：
  Low (146 mg/L)
• 稳定性/保质期：
  STABLE IN LIGHT, AIR & HEAT; HYDROLYZES IN WATER /DANTROLENE SODIUM SALT HYDRATE/
• 解离常数：
  PKA ABOUT 7.5 (FREE ACID)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

肝脏的，最可能是通过肝微粒体酶。在其体液中，其主要代谢物为5-羟基丹特罗林和丹特罗林的乙酰氨基代谢物。另一种结构未知的代谢物似乎与后者有关。丹曲林也可能经历水解和随后的氧化，形成硝基苯基呋喃酸。

Hepatic, most likely by hepatic microsomal enzymes. Its major metabolites in body fluids are 5-hydroxydantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.

来源:DrugBank

代谢

丹曲林通过肝脏混合功能氧化酶系统代谢成5-羟基丹曲林，它与葡萄糖醛酸或硫酸结合。它还通过硝基还原酶代谢成氨曲林，后者抑制肝脏混合功能氧化酶系统。氨曲林的乙酰化作用阻断了其抑制效果。硝基还原酶途径中的中间体形成葡萄糖苷酸和巯基尿酸结合物。巯基尿酸结合反应是丹曲林电负性代谢物的一种解毒机制。

DANTROLENE IS METABOLIZED BY THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM TO 5-HYDROXYDANTROLENE WHICH IS CONJUGATED WITH GLUCURONIC ACID OR WITH SULFATE. IT IS ALSO METABOLIZED BY NITROREDUCTASE TO AMINODANTROLENE WHICH INHIBITS THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM. ACETYLATION OF AMINODANTROLENE BLOCKS THE INHIBITORY EFFECTS. INTERMEDIATES IN THE NITROREDUCTASE PATHWAY FORM GLUCURONIDE & MERCAPTURIC ACID CONJUGATES. THE MERCAPTURIC ACID CONJUGATION REACTION IS A DETOXIFICATION MECHANISM FOR AN ELECTROPHILIC METABOLITE OF DANTROLENE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

轻度的、无症状的血清转氨酶升高在使用丹曲林治疗期间相对不常见（1%），但临床上估计每千人治疗者中会有1到2人发生肝损伤（0.1%到0.2%）。肝损伤可能是严重的；有急性肝衰竭甚至死亡的病例报道（案例1）。临床明显肝损伤的潜伏期从一周到几个月不等，但通常在开始治疗的前6个月内（案例2）。更严重的病例通常突然发作，伴有黄疸、恶心和疲劳，并且病情迅速进展。过敏表现如发热、皮疹和嗜酸性粒细胞增多是罕见的，自身免疫特征也很少见。酶升高的模式主要是肝细胞型。肝脏组织学显示急性肝炎样的图像。通常在1到3个月内完全恢复。女性、老年患者和服用较高剂量的患者似乎更容易发生丹曲林肝毒性。

Mild, asymptomatic serum aminotransferase elevations during dantrolene therapy are relatively uncommon (1%), but clinically over liver injury is estimated to occur in 1 to 2 per thousand treated persons (0.1% to 0.2%). The liver injury can be severe; cases of acute liver failure and even death have been described (Case 1). The latency to onset of clinically apparent liver injury ranges from one week to several months, but is usually within the first 6 months of starting therapy (Case 2). More serious cases are associated with a sudden onset with jaundice, nausea and fatigue, and rapid progression. Allergic manifestations such as fever, rash and eosinophilia are rare, as are autoimmune features. The pattern of enzyme elevations is predominantly hepatocellular. Liver histology demonstrates an acute-hepatitis like picture. Recovery is usually complete within 1 to 3 months. Women, the elderly, and patients taking higher doses appear to be more susceptible to developing dantrolene hepatotoxicity.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：丹曲林

Compound:dantrolene

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：盒子警告

Label Section:Box warning

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

生物利用度为70%。

Bioavailability is 70%.

来源:DrugBank

吸收、分配和排泄

吸收...从胃肠道缓慢且不完全，但足以提供与剂量相关的血浆浓度。成年人体内药物的半衰期约为9小时，服用100毫克剂量后。它被肝脏缓慢代谢，5-羟基和乙酰氨基代谢物与未改变的药物一起通过尿液排出。

ABSORPTION...FROM GI TRACT IS SLOW & INCOMPLETE BUT SUFFICIENTLY CONSISTENT TO PROVIDE DOSE-RELATED PLASMA CONCN. MEAN HALF LIFE OF DRUG IN ADULTS IS ABOUT 9 HR AFTER 100-MG DOSE. IT IS SLOWLY METABOLIZED BY LIVER, & THE 5-HYDROXY & ACETAMIDO METABOLITES ARE EXCRETED WITH UNCHANGED DRUG IN URINE.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  dantrolene 生成 5-(4-硝基苯基)-2-呋喃酸
  参考文献：
  名称：

  WUIS, E. W.;JANSSEN, M. G. A.;VREE, T. B.;KLEIJN, E. VAN DER, J. CHROMATOGR. BIOMED. APPL., 526,(1990) N, C. 575-580

  摘要：

  DOI：
• 作为产物：
  描述：

  5-(tri-n-butylstannyl)-2-furaldehyde 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 作用下， 以 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 dantrolene
  参考文献：
  名称：

  Dantrolene analogues revisited: general synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle

  摘要：

  The general synthesis of dantrolene analogues with various substituents on its phenyl ring has been developed via palladium-catalyzed cross-coupling reactions, the Stille or Suzuki reaction, as the key step. The effects of synthesized analogues have been evaluated by two kinds of Ca2+ release modes from sarcoplasmic reticulum (SR) of mouse skeletal muscle fibers based on: (1) the measurement of twitch contraction caused by the physiological Ca2+ release (PCR) of intact skeletal muscle and (2) the rate of Ca2+-induced Ca2+ release (CICR) in saponin-treated skinned muscle fibers. Although dantrolene, a lead compound, inhibits both twitch contraction and CICR, some structurally modified analogues exhibit one or the other of these effects. The methoxy congener, GIF-0185, potently inhibits the twitch contraction without affecting the CICR, while GIF-0166 and GIF-0248, the ortho-nitro regioisomer and ortho, ortho-dinitro substituted analogues, respectively, doubly potentiate the CICR exclusively. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00600-4

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• [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。
• ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
  申请人：Meng Charles Q.

  公开号：US20140142114A1

  公开（公告）日：2014-05-22

  The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

  本发明涉及以下式（I）的新型驱虫化合物： 其中 Y和Z分别是双环碳环或双环杂环基团，或者Y或Z中的一个是双环碳环或双环杂环基团，另一个是烷基，烯基，炔基，环烷基，苯基，杂环基或杂芳基，以及变量X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 ，X 7 和X 8 如本文所定义。本发明还提供了包含本发明的驱虫化合物的兽药组合物，以及它们用于治疗和预防动物寄生虫感染的用途。
• Piperidinylamino-thieno[2,3-D] pyrimidine compounds
  申请人：Dhanoa S. Dale

  公开号：US20050222176A1

  公开（公告）日：2005-10-06

  The invention relates to 5-HT receptor modulators, particularly 5-HT 2B antagonists. Novel piperidinylamino-thieno [2,3-d] pyrimidine compounds represented by Formula I, II and III, and uses thereof for treating conditions including pulmonary arterial hypertension, congestive heart failure, and hypertension.

  这项发明涉及5-HT受体调节剂，特别是5-HT 2B 拮抗剂。公式I、II和III所代表的新型哌啶基氨基噻吩[2,3-d]嘧啶化合物，以及它们用于治疗包括肺动脉高压、充血性心力衰竭和高血压等疾病的用途。
• [EN] ANTHELMINTIC DEPSIPEPTIDE COMPOUNDS<br/>[FR] COMPOSÉS DEPSIPEPTIDIQUES ANTHELMINTHIQUES
  申请人：MERIAL INC

  公开号：WO2018093920A1

  公开（公告）日：2018-05-24

  The present invention provides cyclic depsipeptide compounds of formula (I) wherein the stereochemical configuration of at least one carbon atom bearing the groups Cy1, Cy2, R1, R2, R3, R4, Ra and Rb is inverted compared with the naturally occurring cyclic depsipeptide PF1022A. The invention also provides compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.

  本发明提供了公式（I）的环状脱氨肽化合物，其中至少一个碳原子的立体化学构型与自然存在的环状脱氨肽PF1022A的基团Cy1、Cy2、R1、R2、R3、R4、Ra和Rb相比发生了倒置。该发明还提供了包含这些化合物的组合物，对危害动物的寄生虫具有有效性。这些化合物和组合物可用于对抗哺乳动物和鸟类体内或体表的寄生虫。该发明还提供了一种改进的方法，用于根除、控制和预防鸟类和哺乳动物的寄生虫感染。