Maralixibat | 716313-53-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫平类
• 英文名称: Maralixibat
• 英文别名: (4R,5R)-5-[4-[[4-(4-aza-1-azoniabicyclo[2.2.2]octan-1-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol
• CAS: 716313-53-0
• 化学式: C40H56N3O4S+
• 分子量: 675.0
• InChiKey: STPKWKPURVSAJF-LJEWAXOPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  48
• 可旋转键数：
  13
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  78.5
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

马拉利昔巴特代谢物在血浆中尚未被识别，但是已经在粪便中回收了3种次要代谢物。这些代谢物的结构在文献中尚未被定义。

Maralixibat metabolites have not been identified in plasma, however 3 minor metabolites have been recovered in the feces. The structure of these metabolites have not been defined in the literature.

来源:DrugBank

毒理性

• 肝毒性

在针对阿拉吉尔综合症儿童进行的maralixibat试验中，24%的患者的血清ALT水平升高到超过正常上限(ULN)的3倍，2%的患者升高到超过5倍ULN。ALT升高导致多达10%的患者需要调整剂量、中断治疗或提前终止治疗。患有阿拉吉尔综合症和其他儿科胆汁淤积性肝病的儿童通常血清转氨酶水平在2到5倍ULN之间波动，很难区分是由基础疾病引起的酶水平自发波动还是maralixibat治疗的影响。在大多数情况下，尽管血清酶水平升高，治疗仍可以继续，至少可以减少剂量。目前还没有因maralixibat治疗而导致黄疸的临床明显肝损伤的报告，但它的总体临床使用有限。

In trials of maralixibat in children with Alagille syndrome, serum ALT levels rose to greater than 3 times ULN in 24% of patients and above 5 times ULN in 2%. The ALT elevations led to dose modification, interruption or therapy or early discontinuation in up to 10% of patients. Children with Alagille syndrome and other pediatric cholestatic liver diseases typically have serum aminotransferase elevations in the range of 2 to 5 times ULN, and it is can be difficult to distinguish between spontaneous fluctuations in enzyme levels due to the underlying disease vs effects of maralixibat therapy. In most instances, therapy can be continued despite the serum enzyme elevations, at least at a reduced dosage. There have been no reports of clinically apparent liver injury with jaundice attributed to maralixibat therapy, but it has had limited general clinical use.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

母乳喂养期间使用的总结：目前没有关于在哺乳期间使用Maralixibat的信息。由于Maralixibat口服吸收不良并且90%与血浆蛋白结合，乳汁中的量可能较低。如果母亲需要Maralixibat，这并不是停止哺乳的理由。 ◉ 对哺乳婴儿的影响：截至修订日期，没有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，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of maralixibat during breastfeeding. Because maralixibat is poorly absorbed orally and 90% bound to plasma proteins, the amount in milk is likely to be low. If maralixibat is required by the mother, it is not a reason to discontinue breastfeeding. ◉ 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

• 蛋白质结合

马莱利昔巴特在体外与血浆蛋白的结合率为91%。

Maralixibat is 91% bound to plasma proteins _in vitro_.

来源:DrugBank

吸收、分配和排泄

• 吸收

马莱利克斯巴特吸收不广泛。在空腹条件下给予单次30毫克马莱利克斯巴特剂量，达到中位Tmax为0.75小时，平均Cmax为1.65 ± 1.10 ng/mL，平均AUClast为3.43 ± 2.13 h*ng/mL。在给予儿科患者380 µg/kg剂量的情况下，最高血清浓度为5.93 ng/mL，但在大多数患者中<0.25 ng/mL。

Maralixibat is not extensively absorbed. A single 30 mg dose of maralixibat given under fasted conditions reached a median Tmax of 0.75 hours, with a mean Cmax of 1.65 ± 1.10 ng/mL, and a mean AUClast of 3.43 ± 2.13 h\*ng/mL. In pediatric patients given a dose of 380 µg/kg, the highest serum concentration was 5.93 ng/mL, but was <0.25 ng/mL in the majority of patients.

来源:DrugBank

吸收、分配和排泄

• 消除途径

一个5毫克的放射性标记的马尔里克斯巴特剂量中有73%通过粪便排出，0.066%通过尿液排出。在粪便中回收的剂量中有94%是未代谢的母化合物。总剂量的不到3%被代谢。

A 5 mg radiolabelled dose of maralixibat is 73% eliminated in feces and 0.066% eliminated in urine. 94% of the dose recovered in the feces was as the unmetabolized parent compound. <3% of the total dose is metabolized.

来源:DrugBank

文献信息

• Bile Acid Recycling Inhibitors for Treatment of Hypercholemia and Cholestatic Liver Disease
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20130108573A1

  公开（公告）日：2013-05-02

  Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了一种治疗或改善高胆固醇血症或胆汁淤积性肝病的方法，即通过向需要的个体施用治疗有效量的顶端钠依赖性胆酸转运蛋白抑制剂（ASBTI）或其药用可接受盐。还提供了一种治疗或改善肝病、降低血清胆酸或肝内胆酸水平、治疗或改善瘙痒、降低肝酶或减少胆红素的方法，即通过向需要的个体施用治疗有效量的ASBTI或其药用可接受盐。
• NOVEL 1,4-BENZOTHIEPIN-1, 1-DIOXIDE DERIVATIVES WITH IMPROVED PROPERTIES METHOD FOR PRODUCING THE SAME, DRUGS CONTAINING SAID COMPOUNDS AND THE USE THEREOF
  申请人：Glombik Heiner

  公开号：US20100035834A1

  公开（公告）日：2010-02-11

  This invention relates to Novel 1,4-benzothiepin-1,1-dioxide derivatives with improved properties, method for producing the same, drugs containing said compounds and use thereof.

  本发明涉及一种具有改进性能的新型1,4-苯并噻吩-1,1-二氧化物衍生物，制备方法，包含该化合物的药物以及其用途。
• Diphenylazetidinone Derivatives Possessing Cholesterol Absorption Inhibitory Activity
  申请人：Alenfalk Susanne

  公开号：US20080064676A1

  公开（公告）日：2008-03-13

  Compounds of formula (I) (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia are described. Processes for their manufacture and pharmaceutical compositions containing them are also described.

  本文描述了化学式(I)的化合物（其中变量基团如定义所示），其药学上可接受的盐、此类盐的溶剂化合物、其前药以及其作为治疗高脂血症的胆固醇吸收抑制剂的用途。本文还描述了其制造工艺和含有它们的制药组合物。
• Diphenylazetidinone derivatives possessing chloesterol absorption inhibitory activity
  申请人：Alenfalk Susanne

  公开号：US20070142304A1

  公开（公告）日：2007-06-21

  Compounds of formula (XV): [Chemical formula should be inserted here. Please see paper copy] (XV) (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia are described. Processes for their manufacture and pharmaceutical compositions containing them are also described.

  化合物的化学式（XV）：[应在此处插入化学式。请参阅纸质副本]（其中变量基团的定义如下），所述化合物的药学上可接受的盐，溶剂化合物，该类盐的溶剂化合物和其前药的用途作为胆固醇吸收抑制剂，用于治疗高脂血症。还描述了其制造过程和含有它们的制药组合物。
• Diphenylazetidinone Derivatives Possessing Cholesterol Absorption Inhibitor Activity
  申请人：Lemurell Malin

  公开号：US20090069285A1

  公开（公告）日：2009-03-12

  2-azetidinone derivatives and pharmaceutical compositions containing them. The compounds are useful in the treatment of hyperlipidemic conditions, atherosclerosis, Alzheimers' disease and cholesterol associated tumours.

  2-azetidinone衍生物及含有它们的制药组合物。这些化合物在治疗高脂血症、动脉粥样硬化、阿尔茨海默病和与胆固醇有关的肿瘤方面是有用的。