3-[(3-三氟甲基)苯基]-5-[(4-羧基苯基)亚甲基]-2-硫代-4-噻唑烷酮 | 307510-92-5

• 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 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 3-[(3-三氟甲基)苯基]-5-[(4-羧基苯基)亚甲基]-2-硫代-4-噻唑烷酮
• 中文别名: 3-[(3-三氟甲基)苯基]-5-[(4-羧基苯基)亚甲基]-2-硫氧代-4-噻唑烷酮
• 英文名称: 4-[[4-oxo-2-sulfanylidene-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-5-ylidene]methyl]benzoic acid
• 英文别名: 4-[[4-oxo-2-thioxo-3-[(3-trifluoromethyl)phenyl]-5-thiazolidinylidene]methyl]benzoic acid；4-[[4-oxo-2-thioxo-3-[3-(trifluoromethyl)phenyl]-5-thiazolidinylidene]methyl]benzoic acid；4-[[4-oxo-2-thioxo-3-[3-trifluoromethyl]phenyl]-5-thiazolidinylidene]methyl benzoic acid；3-[(3-trifluoromethyl) phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone；4-[[4-oxo-2-thioxo-3-[3-trifluoromethylphenyl]-5-thiazolidinylidene]methyl]benzoic acid；3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone；CFTRinh-172
• CAS: 307510-92-5
• 化学式: C₁₈H₁₀F₃NO₃S₂
• 分子量: 409.41
• InChiKey: JIMHYXZZCWVCMI-UHFFFAOYSA-N

物化性质

• 熔点：
  181-183 °C
• 沸点：
  555.7±60.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  8

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi,N
• 安全说明：
  S26,S36/37,S60,S61
• 危险类别码：
  R36/37/38,R43,R50/53
• WGK Germany：
  3
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P501,P273,P260,P270,P264,P280,P391,P314,P337+P313,P305+P351+P338,P301+P312+P330
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410

制备方法与用途

生物活性

CFTRinh-172是一种电势差不依赖性的选择性CFTR抑制剂，其Ki值为300 nM，对MDR1、ATP敏感性钾离子通道以及一系列转运蛋白没有作用。

体外研究

CFTRinh-172表现出时间和剂量依赖性的抑制效果，可以有效抑制CFTR介导的碘离子转运，并且能够有效抑制多种激动剂或活化剂介导的CFTR激活。作为选择性CFTR通道抑制剂，CFTRinh-172能完全阻断兔泪腺腺泡和导管细胞中氯离子的流通。此外，它还通过不依赖于CFTR的机制诱导ROS产生、线粒体损伤以及NF-κB信号通路激活。

体内研究

CFTRinh-172 (20 µg/6 h)在不影响霍乱弧菌体内增殖的情况下能够完全阻碍由霍乱弧菌引起的肠道液体分泌。

靶点

Target	Value
CFTR (in human airway cells)	300 nM(Ki)

体外研究

CFTRinh-172通过时间和剂量依赖性的方式抑制了由CFTR介导的碘离子转运，并有效抑制了多种激动剂或活化剂介导的CFTR激活。作为一种选择性的CFTR通道抑制剂，CFTRinh-172能够完全阻断兔泪腺腺泡和导管细胞中氯离子的流通。此外，它还通过不依赖于CFTR的机制诱导ROS产生、线粒体损伤以及NF-κB信号通路激活。

体内研究

CFTRinh-172 (20 µg/6 h) 在不影响霍乱弧菌体内增殖的情况下能够完全阻断由霍乱弧菌引起的肠道液体分泌。

反应信息

• 作为反应物：
  描述：

  3-[(3-三氟甲基)苯基]-5-[(4-羧基苯基)亚甲基]-2-硫代-4-噻唑烷酮 在 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 反应 2.0h， 生成
  参考文献：
  名称：

  Thiazolidinone CFTR inhibitors with improved water solubility identified by structure–activity analysis

  摘要：

  The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTRinh-172) inhibits cystic fibrosis transmembrane conductance regulator ( CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTRinh-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modi. cations in its two phenyl rings, thiazolidinone core, and core-phenyl connectors. Greatest CFTR inhibition potency was found for 3-CF3 and polar group-substituted-phenyl rings, and a thiazolidinone core. Two compounds with similar to 1 mu M CFTR inhibition potency and solubility >180 mu M(>10-fold more than CFTRinh-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.07.044
• 作为产物：
  描述：

  间氨基三氟甲苯 在 哌啶 碳酸氢钠 、 三乙胺 作用下， 以 乙醇 、 水 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 3-[(3-三氟甲基)苯基]-5-[(4-羧基苯基)亚甲基]-2-硫代-4-噻唑烷酮
  参考文献：
  名称：

  WATER SOLUBLE SMALL MOLECULE INHIBITORS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

  摘要：

  本文提供了高度水溶性的噻唑啉酮衍生物化合物和甘氨酸酰肼衍生物化合物，这些化合物抑制了囊性纤维化跨膜传导调节器（CFTR）的离子传输活性。本文描述的化合物和含有这些化合物的组合物对于治疗与CFTR活性异常增加相关的疾病、紊乱和疾病、紊乱和条件的后遗症非常有用，例如分泌性腹泻。这些化合物也可用于抑制或预防多囊肾病患者囊肿的扩张或形成。

  公开号：

  US20110105565A1

文献信息

• Thiazolidinone CFTR inhibitors with improved water solubility identified by structure–activity analysis
  作者：N.D. Sonawane、A.S. Verkman

  DOI：10.1016/j.bmc.2008.07.044

  日期：2008.9

  The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTRinh-172) inhibits cystic fibrosis transmembrane conductance regulator ( CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTRinh-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modi. cations in its two phenyl rings, thiazolidinone core, and core-phenyl connectors. Greatest CFTR inhibition potency was found for 3-CF3 and polar group-substituted-phenyl rings, and a thiazolidinone core. Two compounds with similar to 1 mu M CFTR inhibition potency and solubility >180 mu M(>10-fold more than CFTRinh-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease. (C) 2008 Elsevier Ltd. All rights reserved.
• WATER SOLUBLE SMALL MOLECULE INHIBITORS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
  申请人：Verkman Alan S.

  公开号：US20110105565A1

  公开（公告）日：2011-05-05

  Provided herein are highly water soluble, thiazolidinone derivative compounds and glycine hydrazide derivative compounds that inhibit the ion transport activity of the cystic fibrosis transmembrane conductance regulator (CFTR). The compounds, and compositions comprising the compounds, described herein are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased CFTR activity, for example, secretory diarrhea. The compounds may also be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

  本文提供了高度水溶性的噻唑啉酮衍生物化合物和甘氨酸酰肼衍生物化合物，这些化合物抑制了囊性纤维化跨膜传导调节器（CFTR）的离子传输活性。本文描述的化合物和含有这些化合物的组合物对于治疗与CFTR活性异常增加相关的疾病、紊乱和疾病、紊乱和条件的后遗症非常有用，例如分泌性腹泻。这些化合物也可用于抑制或预防多囊肾病患者囊肿的扩张或形成。