VX-661/VX6611-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N-[1-[(2R)-2,3-二羟基丙基]-6-氟-2-(2-羟基-1,1-二甲基乙基)-1H-吲哚-5-基]-环丙烷甲酰胺 | 1152311-62-0

• 物质功能分类: 生物化工 - 抑制剂 - 跨膜转运体(Transmembrane Transporters)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: VX-661/VX6611-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N-[1-[(2R)-2,3-二羟基丙基]-6-氟-2-(2-羟基-1,1-二甲基乙基)-1H-吲哚-5-基]-环丙烷甲酰胺
• 中文别名: 1-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N-[1-[(2R)-2,3-二羟基丙基]-6-氟-2-(2-羟基-1,1-二甲基乙基)-1H-吲哚-5-基]-环丙烷甲酰胺
• 英文名称: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
• 英文别名: tezacaftor；VX-661；1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide；1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide
• CAS: 1152311-62-0
• 化学式: C₂₆H₂₇F₃N₂O₆
• 分子量: 520.505
• InChiKey: MJUVRTYWUMPBTR-MRXNPFEDSA-N

物化性质

• 沸点：
  610.8±55.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO 中≥21.8 mg/mL；不溶于乙醇；水中≥24.3 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  113
• 氢给体数：
  4
• 氢受体数：
  9

ADMET

代谢

Tezacaftor在人体内通过CYP3A4和CYP3A5的作用被广泛代谢。主要有三种循环代谢物；M1、M2和M5。M1是一种具有与母药Tezacaftor相似活性的活性代谢物。M2代谢物的活性显著较低，而M5被认为是一种非活性代谢物。[A179665,L6814] 另一种循环代谢物M3，对应于Tezacaftor的葡萄糖醛酸形式。[L6814]

Tezacaftor is metabolized extensively in humans by the action of CYP3A4 and CYP3A5. There are three main circulating metabolites; M1, M2, and M5. The M1 is an active metabolite with similar activity to the parent drug, tezacaftor. The M2 metabolite is significantly less active and M5 is considered an inactive metabolite.[A179665,L6814] An additional circulating metabolite, M3, corresponding to the glucuronide form of tezacaftor.[L6814]

来源:DrugBank

毒理性

• 肝毒性

在大规模随机对照试验中，使用伊瓦卡托（ivacaftor）单药或与卢玛卡托（lumacaftor）或特扎卡托（tezacaftor）联合使用，多达25%的受试者在治疗期间出现了不同程度的血清转氨酶升高。然而，这些升高通常是短暂的、轻微的，并且只有2%到5%的患者超过正常上限（ULN）的3倍。这些异常通常无症状，并且经常在不调整剂量的情况下自发解决。此外，在几项研究中，安慰剂治疗组也观察到了类似的血清酶升高率。尽管如此，伊瓦卡托治疗的患者中有1%到2%因血清转氨酶升高而调整了剂量或中断了治疗。在伊瓦卡托和卢玛卡托联合使用的上市前临床试验中，报告了更高的血清酶升高率，并且有3名患者同时出现了胆红素升高（超过2倍ULN）。肝损伤的临床特征，如发病时间、胆红素或血清酶升高的高度、停药或调整剂量的反应和结果没有描述。自从这些药物获得批准并更广泛使用以来，没有发表过归因于伊瓦卡托或其与卢玛卡托联合使用的明显临床肝损伤的案例报告，但这两种药物仅短期可用且使用患者数量有限。使问题复杂化的是，CF患者通常会有轻微的血清酶升高，这种升高可能是短暂的、间歇性的，但有时是持续的，甚至伴有胆红素升高。一部分CF患者会发展为严重的肝病，伴有门脉高压和明显的肝功能障碍。

In large randomized controlled trials of ivacaftor with or without lumacaftor or tezacaftor, up to 25% of subjects had some degree of serum aminotransferase elevations during therapy. The elevations, however, were generally transient and mild and were above 3 times the upper limit of normal (ULN) in only 2% to 5% of patients. The abnormalities were usually asymptomatic and often resolved spontaneously without dose adjustment. Furthermore, in several studies, similar rates of serum enzyme elevations were noted in the placebo treated groups. Nevertheless, serum aminotransferase elevations resulted in dose modification or interruption in 1% to 2% of patients on ivacaftor. In prelicensure clinical trials of the combination of ivacaftor and lumacaftor, a higher rate of serum enzyme elevations was reported, and 3 patients had concurrent bilirubin elevations (above 2 times ULN). The clinical features of the liver injury such as the timing of onset, height of bilirubin or serum enzyme elevations, response to discontinuation or dose modification and outcomes were not described. Since approval of these agents and their more widescale use, there have no published case reports of clinically apparent liver injury attributed to ivacaftor or its combination with lumacaftor, but both have been available for a short time only and used in a limited number of patients. Complicating the issue is that patients with CF often have mild serum enzyme elevations that can be transient and intermittent, but are sometimes persistent and even accompanied by bilirubin elevations. A proportion of patients with CF develop severe liver disease with portal hypertension and marked hepatic dysfunction.

来源:LiverTox

毒理性

• 毒性总结

大鼠口服剂量的LD50大于2000毫克/千克。[L6826] 过量症状可能包括头晕和腹泻。截至目前，尚未收到关于tezacaftor过量的报告，但最高剂量450毫克每12小时通常会导致头晕和腹泻的报告。这种药物过量没有解毒剂。应采取一般支持性措施，并监测生命体征和密切监测临床状况。[L6814]

The LD50 of an oral dose in rats is >2000 mg/kg.[L6826] Overdose symptoms may include dizziness and diarrhea. There have been no reports to this date of tezacaftor overdose, but the highest dose of 450 mg every 12 hours commonly resulted in reports of dizziness and diarrhea. No antidote exists for treating an overdose with this drug. General supportive measures should be undertaken along with monitoring of vital signs and close monitoring of clinical status.[L6814]

来源:DrugBank

毒理性

• 蛋白质结合

Tezacaftor大约有99%与血浆蛋白结合，主要是白蛋白。

Tezacaftor is approximately 99% bound to plasma proteins, mainly albumin.[L6814]

来源:DrugBank

吸收、分配和排泄

• 吸收

Cmax、Tmax 和 AUC 分别为 5.95 mcg/ml、2-6 小时和 84.5 mcg·h/ml。当与高脂肪餐一起服用时，tezacaftor/ivacaftor 的暴露量会增加 3 倍。

The Cmax, Tmax and AUC of tezacaftor, when administered with ivacaftor, are 5.95 mcg/ml, 2-6 h, and 84.5 mcg.h/ml respectively.[L6814] Exposure of tezacaftor/ivacaftor increases 3-fold when it is administered with a high-fat meal.[L6814]

来源:DrugBank

吸收、分配和排泄

• 消除途径

经口服给药后，大部分的tezacaftor剂量（72%）以原形或其代谢物M2的形式在粪便中被发现排出。大约14%的给药剂量以代谢物M2的形式在尿液中排出。注意到不到1%的给药剂量以原形在尿液中排出，因此肾脏排泄不是主要的消除途径。

After oral administration, the majority of tezacaftor dose (72%) is found excreted in the feces either unchanged or as its metabolite, M2. About 14% of the administered dose is found excreted in the urine as the metabolite, M2. It was noted that less than 1% of the administered dose is excreted unchanged in the urine and thus, renal excretion is not the major elimination pathway.[L6814]

来源:DrugBank

吸收、分配和排泄

• 分布容积

在研究中，接受每12小时100毫克tezacaftor的饱腹状态患者的tezacaftor表观分布体积为271升。[L6814]

The apparent volume of distribution of tezacaftor was 271 L in a study of patients in the fed state who received 100 mg of tezacaftor every 12 hours.[L6814]

来源:DrugBank

吸收、分配和排泄

• 清除

在临床试验中，已测量了饱腹状态下患者的替扎卡福尔表观清除率为1.31升/小时。[A32094]

The apparent clearance of tezacaftor has been measured at 1.31 L/h for patients in the fed state during a clinical trial.[A32094]

来源:DrugBank

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20℃

制备方法与用途

生物活性

Tezacaftor（VX-661）是第二个用于校正F508del-CFTR蛋白的药物，能够帮助CFTR蛋白到达细胞表面。它处于二期临床阶段。

靶点

Target	Value
F508del-CFTR (Cell-free assay)

体外研究

VX-661是一种CFTR校正药物，能够使携带F508del突变的通道避免被降解，并转运到细胞膜上。

反应信息

• 作为反应物：
  描述：

  VX-661/VX6611-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N-[1-[(2R)-2,3-二羟基丙基]-6-氟-2-(2-羟基-1,1-二甲基乙基)-1H-吲哚-5-基]-环丙烷甲酰胺 在 戴斯-马丁氧化剂 、 sodium sulfite 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 4.0h， 以15%的产率得到1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-((4R)-8-fluoro-2-hydroxy-4-(hydroxymethyl)-1,1-dimethyl-1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-α]indol-9-yl)cyclopropane carboxamide
  参考文献：
  名称：

  MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

  摘要：

  本发明的化合物及其药学上可接受的组合物，可用作调节ATP结合盒转运蛋白（“ABC”）或其片段的调节剂，包括囊性纤维化跨膜传导调节蛋白（“CFTR”）。本发明还涉及使用本发明的化合物治疗ABC转运蛋白介导的疾病的方法。

  公开号：

  US20130116238A1
• 作为产物：
  描述：

  在 氢气 作用下， 以 乙腈 为溶剂， 40.0~45.0 ℃ 、400.01 kPa 条件下， 反应 4.0h， 以96.1%的产率得到VX-661/VX6611-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N-[1-[(2R)-2,3-二羟基丙基]-6-氟-2-(2-羟基-1,1-二甲基乙基)-1H-吲哚-5-基]-环丙烷甲酰胺
  参考文献：
  名称：

  一种5-取代环丙基甲酰氨基吲哚衍生物的制 备方法

  摘要：

  本发明提供一种5‑取代环丙基甲酰氨基吲哚衍生物的制备方法，具体指一种Tezacaftor的制备方法。利用2‑硝基‑4‑氟‑5‑卤代苯乙腈为起始原料，经氨取代反应、酰胺化反应、脱水缩合反应、还原环合反应‑消除反应、开环取代反应和催化氢解反应得到Tezacaftor。本发明的方法原料廉价易得，反应步骤短，制备方法简便安全，易于实现，成本低；本发明路线的设计充分结合了官能团反应的固有特性，确保每步单元反应活性适宜，选择性高，为产品的高收率和高纯度提供了本质上的保证；本发明路线原子经济性高，产物收率和纯度高，废酸废水产生量少，绿色环保，适合工业化生产。

  公开号：

  CN111763198B

文献信息

• Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20150231142A1

  公开（公告）日：2015-08-20

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及含有上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use
  申请人：AbbVie S.à.r.l.

  公开号：US20190077784A1

  公开（公告）日：2019-03-14

  The invention discloses compounds of Formula (I), wherein A 1 , R 1 , R 2 , R 3 , R 4 , and n are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

  该发明揭示了式（I）的化合物， 其中A 1 ，R 1 ，R 2 ，R 3 ，R 4 和n如本文所定义。本发明涉及化合物及其在囊性纤维化治疗中的应用，其生产方法，包含相同化合物的药物组合物，以及通过给予该发明的化合物来治疗囊性纤维化的方法。
• COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
  申请人：Van Goor Fredrick F.

  公开号：US20110098311A1

  公开（公告）日：2011-04-28

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及包含上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
  申请人：VERTEX PHARMACEUTICALS INCORPORATED

  公开号：US20160095858A1

  公开（公告）日：2016-04-07

  The present invention features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.

  本发明涉及一种具有以下化学式I的化合物： 或其药用可接受的盐，其中R 1 ，R 2 ，R 3 ，W，X，Y，Z，n，o，p和q在此处定义，用于治疗CFTR介导的疾病，如囊性纤维化。本发明还涉及药物组合物、治疗方法和相关工具包。
• MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20210047350A1

  公开（公告）日：2021-02-18

  This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.

  本公开提供了囊性纤维化跨膜电导调节剂（CFTR）的调节剂，包含至少一种此类调节剂的药物组合物，使用此类调节剂和药物组合物治疗囊性纤维化的方法，以及制造此类调节剂的过程。