1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl})carbamoylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine | 501692-44-0

• 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
• 英文名称: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl})carbamoylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
• 英文别名: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine；1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine；Odevixibat；(2S)-2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,2,5-benzothiadiazepin-8-yl)oxy]acetyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]butanoic acid
• CAS: 501692-44-0
• 化学式: C₃₇H₄₈N₄O₈S₂
• 分子量: 740.942
• InChiKey: XULSCZPZVQIMFM-IPZQJPLYSA-N

物化性质

• 密度：
  1.34±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：166.67 mg/mL（224.95 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  51
• 可旋转键数：
  17
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  208
• 氢给体数：
  5
• 氢受体数：
  11

ADMET

代谢

Odevixibat 大部分未代谢，然而，有一小部分在体外通过单一羟基化代谢。代谢物的确切结构尚未被表征，因为临床试验的主要终点是表征血浆、尿液或粪便中剂量超过10%的代谢物的结构。没有发现如此高浓度的代谢物。

Odevixibat is largely unmetabolized, however a small amount is metabolized _in vitro_ by mono-hydroxylation. The exact structure of the metabolite has not been characterized as a primary endpoint of the clinical trial was to characterize the structure of metabolites accounting for >10% of the dose in plasma, urine, or feces. No metabolites have been identified at such a high concentration.

来源:DrugBank

毒理性

• 肝毒性

在针对胆汁淤积性肝病儿童进行的odevixibat临床试验中，有8%至11%的受试者出现了血清ALT水平升高超过正常上限3倍的情况，长期治疗时这种情况尤为常见。然而，患有PFIC（进行性家族性肝内胆汁淤积症）的儿童通常会出现血清ALT和AST升高，因此很难确定轻至中度的血清酶水平升高是否是由于odevixibat治疗还是由于基础疾病自然波动所导致。在接受odevixibat治疗的儿童中尚未报告出现黄疸或肝功能衰竭的临床明显肝损伤，尽管使用该药物的临床经验总体上是有限的。

In trials of odevixibat in children with cholestatic liver diseases, serum ALT elevations of greater than 3 times ULN arose in 8% to 11% of treated participants and were particularly common with long term therapy. However, children with PFIC typically have serum ALT and AST elevations, and it was difficult to establish whether mild-to-moderate serum enzyme elevations were due to odevixibat therapy or to the spontaneous fluctuations that occur with the underlying disease. Clinically apparent liver injury with jaundice or hepatic decompensation has not been reported in children treated with odevixibat, although the total clinical experience with its use is limited.

来源:LiverTox

毒理性

• 蛋白质结合

由于奥德维西巴特（odevixibat）的系统吸收较低，无法在体内进行血浆蛋白结合研究。在体外，奥德维西巴特与蛋白质的结合率超过99%。

Due to the low systemic abosrption of odevixibat, plasma protein binding studies could not be performed _in vivo_. Odevixibat is >99% protein bound _in vitro_.

来源:DrugBank

吸收、分配和排泄

• 吸收

成人口服单剂量7.2毫克的奥德维西巴特，达到Cmax为0.47纳克/毫升，AUC0-24h为2.19小时*纳克/毫升。大多数成人和儿科患者在给予治疗剂量后，血浆中检测不到奥德维西巴特的浓度。

A 7.2 mg single oral dose of odevixibat in adults reaches a Cmax of 0.47 ng/mL, with an AUC0-24h of 2.19 h\*ng/mL. The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Odevixibat 在粪便中回收率为82.9%，在尿液中回收率小于0.002%。在粪便中回收的剂量中，有97%是未改变的母化合物。

Odevixibat is 82.9% recovered in the feces and <0.002% recovered in the urine. The dose recovered in the feces is 97% unchanged parent compound.

来源:DrugBank

吸收、分配和排泄

• 分布容积

大多数成人和儿科患者在给予治疗剂量后，血浆中奥德维西巴特的浓度是不可检测的。因此，尚未计算分布容积。

The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, a volume of distribution has not been calculated.

来源:DrugBank

吸收、分配和排泄

• 清除

大多数成人和儿科患者在给予治疗剂量后，血浆中奥德维西巴特的浓度是不可检测的。因此，尚未计算清除率。

The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, the clearance has not been calculated.

来源:DrugBank

安全信息

• 储存条件：
  -20°C，惰性气体

制备方法与用途

A4250（也称为Odevixibat）是一种小分子回肠胆汁酸转运蛋白（IBAT）抑制剂，用于治疗胆汁淤积性肝病，包括进行性家族性肝内胆汁淤积和非酒精性脂肪性肝炎。正在进行的临床试验探索其其他适应症。

反应信息

• 作为反应物：
  描述：

  2-甲基-3-羟基-4,5-二羟甲基吡啶 、 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl})carbamoylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 以 丙醇 为溶剂， 生成
  参考文献：
  名称：

  COCRYSTALS OF ODEVIXIBAT

  摘要：

  The present invention relates to a cocrystal of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- {(R)-α-[N-((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine (odevixibat) and pyridoxine. The invention also relates to a pharmaceutical composition comprising said cocrystal, and to its use in the treatment of various conditions as described herein.

  公开号：

  WO2024121431A1
• 作为产物：
  描述：

  1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 在 N-甲基吗啉 、 2,6-二甲基吡啶 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.67h， 生成 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl})carbamoylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
  参考文献：
  名称：

  BENZOTHIAZEPINE AND BENZOTHIADIAZEPINE DERIVATIVES WITH ILEAL BILE ACID TRANSPORT (IBAT) INHIBITORY ACTIVITY FOR THE TREATMENT HYPERLIPIDAEMIA

  摘要：

  公开号：

  EP1427423B9

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。
• [EN] DIPHENYLAZETIDINONE DERIVATES POSSESSING CHOLESTEROL ABSORPTION INHIBITORY ACTIVITY<br/>[FR] DERIVES DIPHENYLAZETIDINONE A ACTIVITE INHIBITRICE DE L'ABSORPTION DU CHOLESTEROL
  申请人：ASTRAZENECA AB

  公开号：WO2005061452A1

  公开（公告）日：2005-07-07

  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.

  化合物的结构式（其中变量基团如定义所示）及其药学上可接受的盐、溶剂合物、该类盐的溶剂合物和它们的前药，以及它们作为治疗高脂血症的胆固醇吸收抑制剂的用途被描述。还描述了它们的制备方法和含有它们的药物组合物。
• [EN] ORTHO-SUBSTITUTED BENZOIC ACID DERIVATIVES FOR THE TREATMENT OF INSULIN RESISTANCE<br/>[FR] DERIVES DE L'ACIDE BENZOIQUE ORTHO-SUBSTITUES DESTINES AU TRAITEMENT DE L'INSULINORESISTANCE
  申请人：ASTRAZENECA AB

  公开号：WO2004000294A1

  公开（公告）日：2003-12-31

  The present invention provides a compound of formula (I), wherein n is 0, 1 or 2; R1 represents halo, a C1-4alkyl group which is optionally substituted by one or more fluoro, a C1-4alkoxy group which is optionally substituted by one or more fluoro and wherein when n is 2 the substituents R1 may be the same or different; R2 represents an unbranched C2-7alkyl group; R3 represents H or OCH3; and W represents O or S and pharmaceutically acceptable salts and prodrugs thereof, to processes for preparing such compounds, to their utility in treating clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.

  本发明提供了一种式(I)化合物，其中n为0、1或2；R1代表卤素、可被一个或多个氟取代的C1-4烷基、可被一个或多个氟取代的C1-4烷氧基，且当n为2时，取代基R1可以相同或不同；R2代表直链C2-7烷基；R3代表H或OCH3；W代表O或S及其药学上可接受的盐和前药，以及制备此类化合物的方法，它们在治疗与胰岛素抵抗相关的临床条件中的用途，其治疗方法以及含有它们的药物组合物。
• [EN] AMINE SALTS OF (-)-2-{`2-(4-HYDROXYPHENYL) ETHYL!-THIO}-3-`4-(2-{4-`(METHYLSULFONYL)OXY! PHENOXY}ETHYL)PHENYL! PROPANOIC ACID AND THERE USE IN MEDICINE<br/>[FR] SELS AMINE D'ACIDE (-)-2-{`2-(4-HYDROXYPHENYL)ETHYL!-THIO}-3-`4-(2-{4-`(METHYLSULFONYL)OXY!PHENOXY}ETHYL)PHENYL!PROPANOIQUE ET LEUR UTILISATION EN MEDECINE
  申请人：ASTRAZENECA AB

  公开号：WO2004113283A1

  公开（公告）日：2004-12-29

  A tert-butylamine salt, a piperazine salt, a choline salt, a tris(hydroxymethyl)methylamine salt, a lysine salt or an adamantylamine salt of (-)-2-[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoic acid processes for their preparation, their use in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance and other manifestations of the metabolic syndrome, and pharmaceutical compositions containing them.

  一种(-)-2-[2-(4-羟基苯基)乙基]硫基}-3-[4-(2-4-[(甲磺氧基)氧基]苯氧基}乙基)苯基]丙酸的叔丁胺盐、哌嗪盐、胆碱盐、三(羟甲基)甲基胺盐、赖氨酸盐或金刚烷胺盐的制备方法，以及它们在治疗临床病症中的应用，包括与胰岛素抵抗和代谢综合征其他表现有关的脂质紊乱（脂质代谢异常），以及含有它们的药物组合物。
• Therapeutic agents
  申请人：Alstermark Lindstedt Eva-Lotte

  公开号：US20050282822A1

  公开（公告）日：2005-12-22

  The present invention provides a compound of formula I processes for preparing such compounds, their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance, methods for their therapeutic use and pharmaceutical compositions containing them.

  本发明提供了一种I式化合物，以及制备这种化合物的方法，它们在治疗临床病症中的应用，包括与胰岛素抵抗有关的脂质紊乱（脂质代谢异常），以及它们的治疗用途和含有它们的药物组合物。