3-[5-(2-氟苯基)-1,2,4-恶二唑-3-基]苯甲酸 | 775304-57-9

• 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 - 唑类
• 中文名称: 3-[5-(2-氟苯基)-1,2,4-恶二唑-3-基]苯甲酸
• 中文别名: 阿塔鲁伦
• 英文名称: ataluren
• 英文别名: 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid；PTC-124；translarna；3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
• CAS: 775304-57-9
• 化学式: C₁₅H₉FN₂O₃
• 分子量: 284.246
• InChiKey: OOUGLTULBSNHNF-UHFFFAOYSA-N

物化性质

• 熔点：
  241 - 242°C
• 沸点：
  503.7±60.0 °C(Predicted)
• 密度：
  1.379
• 溶解度：
  二甲基亚砜（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  76.2
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

阿塔鲁伦通过尿苷二磷酸葡萄糖醛酸基转移酶（UGT）酶的共轭作用在肝脏和小肠中被代谢，主要是UGT1A9。在体内，口服放射性标记的阿塔鲁伦后，在血浆中检测到的唯一代谢物是阿塔鲁伦-O-1β-酰基葡萄糖醛酸苷；人体内这种代谢物的暴露量大约是阿塔鲁伦血浆AUC的8%。

Ataluren is metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, predominantly UGT1A9 in liver and intestine. In vivo, the only metabolite detected in plasma after oral administration of radio-labelled ataluren was the ataluren-O-1β-acyl glucuronide; exposure to this metabolite in humans was approximately 8% of the plasma AUC of ataluren.

来源:DrugBank

毒理性

• 蛋白质结合

阿塔鲁伦（Ataluren）有99.6%与人类血浆蛋白结合，这种结合与血浆浓度无关。阿塔鲁伦不会分布进入红细胞。

Ataluren is 99.6% bound to human plasma proteins and the binding is independent of plasma concentration. Ataluren does not distribute into red blood cells.

来源:DrugBank

吸收、分配和排泄

• 吸收

在饭后30分钟内服用药物的受试者中，ataluren的峰值血浆水平大约在给药后1.5小时达到。

Peak plasma levels of ataluren are attained approximately 1.5 hours after dosing in subjects who received medicinal product within 30 minutes of a meal.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在给予单次口服放射性标记的阿塔鲁伦后，大约一半的放射性剂量在粪便中回收，其余在尿液中回收。在尿液中，未改变的阿塔鲁伦和乙酰葡萄糖醛酸苷代谢物分别占给药剂量的不到1%和49%。

After a single oral dose of radiolabeled ataluren, approximately half of the administered radioactive dose is recovered in the faeces and the remainder was recovered in the urine. In the urine, unchanged ataluren and the acyl glucuronide metabolite account for less than 1% and 49%, respectively, of the administered dose.

来源:DrugBank

安全信息

• 海关编码：
  2934999090
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  室温且干燥

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Ataluren
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Ataluren
CAS number: 775304-57-9

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C15H9FN2O3
Molecular weight: 284.2

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, hydrogen fluoride.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

PTC124 具有口服生物有效性，并且具有适当的安全毒性谱。Ataluren (PTC124) 选择性诱导核糖体转录通读，而不影响正常的终止密码子。在HEK293细胞中，其EC50为0.1 μM。PTC124 可以治疗由 nonsense mutations（如CFTR无义突变引起的囊性纤维化）导致的家族遗传性疾病，并已进入第三阶段临床试验。

靶点

• 目标: CFTR (nonsense mutant) (HEK293 cells)

体外研究 与 gentamicin 相比，PTC124 是更有效的无义抑制剂，在较低浓度下就能表现出显著活性。PTC124（0.01-3 μM）作用于含有 LUC-190 无义等位基因的 HEK293 细胞时，可以促进三个无义密码子的通读，并且存在剂量依赖性，UGA 通读最高，其次是 UAG，然后是 UAA。此外，PTC124 在嘧啶处（尤其是胞嘧啶 C）的活性最高。这些发现与稳定细胞系报告实验一致：在 Duchenne 肌营养不良症 (DMD) 患者或表达肌萎缩蛋白无义等位基因的 mdx 小鼠中，PTC124 以 17 μM 的剂量显著促进了肌萎缩蛋白产量。即使浓度远高于达到最大活性所需值，PTC124 仍然选择性促进核糖体对提前终止密码子而非正常终止密码子的通读。

体内研究 由于能恢复肌萎缩蛋白产量的功能性表达，PTC124 按口服、腹腔注射或两者联合处理 mdx 小鼠 2-8 周后，部分缓解了营养不良肌肉中的功能性力量不足。这些作用主要体现在趾长伸肌（EDL），并显著降低了血清肌酸激酶值。在表达人类 CFTR-G542X 转基因的 Cftr-/- 小鼠中，以 ~60 mg/kg 的剂量进行皮下或口服处理后，PTC124 有效地抑制了 G542X 无义突变，并表现出剂量依赖性作用。这导致人类 (h)CFTR 蛋白表达和功能显著恢复，而对无义介导的 mRNA 降解（NMD）或其他方面没有任何影响。在 Cftr+/+ 小鼠中，以 60 mg/kg 的剂量处理后观察到正常肠道跨上皮 cAMP 刺激的短路电流恢复了约29%，这一效果明显优于 gentamicin。

反应信息

• 作为反应物：
  描述：

  3-[5-(2-氟苯基)-1,2,4-恶二唑-3-基]苯甲酸 在 potassium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid potassium salt
  参考文献：
  名称：

  [EN] PHARMACEUTICAL COMPOSITIONS AND SALTS OF A 1,2,4-OXADIAZOLE BENZOIC ACID
  [FR] COMPOSITIONS PHARMACEUTIQUES ET SELS D'UN ACIDE BENZOÏQUE 1,2,4-OXADIAZOLE

  摘要：

  本文提供了药物组合物，其中包括1,2,4-噁二唑苯甲酸或其药学上可接受的盐。本文还提供了某些药学上可接受的1,2,4-噁二唑苯甲酸盐及其制备方法。本文还提供了治疗或预防与无意义突变或过早终止密码子相关的疾病的方法，包括向患有与无意义突变或过早终止密码子相关的疾病的患者施用此类药物组合物或药学上可接受的盐。

  公开号：

  WO2015134711A1
• 作为产物：
  描述：

  3-(N'-((2-fluorobenzoyl)oxy)carbamimidoyl)benzoic acid 以 叔丁醇 为溶剂， 反应 24.0h， 以88.4%的产率得到3-[5-(2-氟苯基)-1,2,4-恶二唑-3-基]苯甲酸
  参考文献：
  名称：

  PROCESS FOR PREPARING ATALUREN AND ITS INTERMEDIATES

  摘要：

  本发明提供了制备阿塔卢伦的工艺。还提供了制备阿塔卢伦的中间体。

  公开号：

  US20170362192A1

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。
• 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。
• [EN] 5-MEMBERED HETEROARYLAMINOSULFONAMIDES FOR TREATING CONDITIONS MEDIATED BY DEFICIENT CFTR ACTIVITY<br/>[FR] HÉTÉROARYLAMINOSULFONAMIDES À 5 CHAÎNONS POUR LE TRAITEMENT D'ÉTATS À MÉDIATION PAR UNE ACTIVITÉ CFTR DÉFICIENTE
  申请人：GENZYME CORP

  公开号：WO2021097057A1

  公开（公告）日：2021-05-20

  The invention relates to heteroaryl compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.

  这项发明涉及杂环芳基化合物，其药用盐以及药物制剂。本文还描述了这些化合物的组成以及在治疗由CFTR活性不足介导的疾病和病况的方法中的使用，特别是囊性纤维化。
• [EN] ARYLAMIDES AND METHODS OF USE THEREOF<br/>[FR] ARYLAMIDES ET LEURS PROCÉDÉS D'UTILISATION
  申请人：GENZYME CORP

  公开号：WO2021113809A1

  公开（公告）日：2021-06-10

  The present disclosure relates to heterocyclic compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.

  本公开涉及杂环化合物，其药用盐以及药物制剂。本文还描述了这些化合物的组成以及在治疗由CFTR活性不足介导的疾病和病况的方法中的使用，特别是囊性纤维化。