cemtirestat | 309283-89-4

• 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
• 英文名称: cemtirestat
• 英文别名: 2-(3-thioxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl)acetic acid；2-(3-thioxo-2,3-dihydro-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid；CMTI；(3-Thioxo-2,3-Dihydro-5h-[1,2,4]triazino[5,6-B]indol-5-Yl)acetic Acid；2-(3-sulfanylidene-2H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid
• CAS: 309283-89-4
• 化学式: C₁₁H₈N₄O₂S
• mdl: MFCD01820802
• 分子量: 260.276
• InChiKey: LCMDWJXBUZDEKA-UHFFFAOYSA-N

物化性质

• 沸点：
  546.9±56.0 °C(Predicted)
• 密度：
  1.70±0.1 g/cm3(Predicted)
• 溶解度：
  22 [ug/mL]

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  cemtirestat 在 potassium permanganate 、 sodium hydroxide 作用下， 以 水 为溶剂， 反应 0.5h， 以89%的产率得到2-(3-oxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl)acetic acid
  参考文献：
  名称：

  醛糖还原酶的新型氧代三嗪并吲哚抑制剂的开发：硫代三唑并吲哚西替司他中的等位硫/氧替代显着提高了抑制选择性。

  摘要：

  抑制醛糖还原酶（AR），多元醇途径的第一种酶，是治疗糖尿病并发症的一种有前途的方法。我们通过用氧气替代硫来优化新型AR抑制剂西非司他的硫代三嗪并吲哚骨架。通过分子建模和对接设计了一系列2-（3-oxo-2H- [1,2,4] triazino [5,6-b]吲哚-5（3H）-基）乙酸衍生物（OTI），被合成。与原始的硫代三嗪并吲哚同类物的硫相比，OTI的负电性更高且体积较小的氧被发现与AR的Leu300形成更强的H键，并使羧甲基药效团具有更大的旋转柔韧性。通过在亚微摩尔范围内的IC 50值来表征新化合物的AR抑制活性。记录了相对于结构相关的醛还原酶的抑制选择性显着提高。综上所述，通过用氧与可变N（2）简单取代基进行氧的硫的等位取代，对原始羧甲基化硫代三嗪并吲哚西替司他的结构修饰提供了新的类似物，其AR抑制作用增强，选择性显着提高。

  DOI：

  10.1021/acs.jmedchem.9b01747
• 作为产物：
  描述：

  2,3-二氢-2,3-二氧代-1H-吲哚-1-乙酸乙酯 在 potassium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 cemtirestat
  参考文献：
  名称：

  醛糖还原酶的新型氧代三嗪并吲哚抑制剂的开发：硫代三唑并吲哚西替司他中的等位硫/氧替代显着提高了抑制选择性。

  摘要：

  抑制醛糖还原酶（AR），多元醇途径的第一种酶，是治疗糖尿病并发症的一种有前途的方法。我们通过用氧气替代硫来优化新型AR抑制剂西非司他的硫代三嗪并吲哚骨架。通过分子建模和对接设计了一系列2-（3-oxo-2H- [1,2,4] triazino [5,6-b]吲哚-5（3H）-基）乙酸衍生物（OTI），被合成。与原始的硫代三嗪并吲哚同类物的硫相比，OTI的负电性更高且体积较小的氧被发现与AR的Leu300形成更强的H键，并使羧甲基药效团具有更大的旋转柔韧性。通过在亚微摩尔范围内的IC 50值来表征新化合物的AR抑制活性。记录了相对于结构相关的醛还原酶的抑制选择性显着提高。综上所述，通过用氧与可变N（2）简单取代基进行氧的硫的等位取代，对原始羧甲基化硫代三嗪并吲哚西替司他的结构修饰提供了新的类似物，其AR抑制作用增强，选择性显着提高。

  DOI：

  10.1021/acs.jmedchem.9b01747

文献信息

• Cu(II) mediated oxidation of cemtirestat yields its disulfide under physiological conditions in vitro
  作者：Pavol Bodo、Lucia Kovacikova、Andrej Bohac、Milan Stefek

  DOI：10.1007/s11696-022-02368-w

  日期：2022.11

  under physiological conditions in vitro. UV–Vis spectral changes of cemtirestat (50 µM) in the presence of increasing concentrations of CuCl2 in 1.0 mM phosphate buffer at pH 7.4 were characterized by time dependent decrease in the cemtirestat base peak at 302 nm and concurrent increase in a novel peak at 270 nm. The titration equivalence point determined at 25 µM CuCl2 indicates that 1 mol of CuCl2

  本研究的目的是研究cemtirestat（一种有效的醛糖还原酶抑制剂和抗氧化剂）在体外生理条件下与Cu 2+离子的相互作用。在 pH 7.4 的 1.0 mM 磷酸盐缓冲液中，随着 CuCl 2浓度的增加，cemtirestat (50 µM) 的 UV-Vis 光谱变化的特征是在 302 nm 处的 cemtirestat 基峰随时间降低，同时在270 纳米。在 25 µM CuCl 2下测定的滴定当量点表明 1 mol CuCl 2与 2 mol cemtirestat 相互作用。在还原剂三（2-羧乙基）膦（TCEP，1 mM）存在下，新产品在 270 nm 处的 UV-Vis 峰移回 302 nm（对应于西姆替司他）。结果表明 Cu(II) 介导的 cemtirestat 氧化为其二硫化物。通过将 TLC 保留数据和 UV-Vis/质谱与标准独立合成的二硫化西姆替司他进行比较，证实了
• [EN] USE OF 5-CARBOXYMETHYL-3-MERCAPTO-1,2,4-TRIAZINO-[5,6-B]INDOLES AND THEIR PHARMACEUTICAL COMPOSITION<br/>[FR] UTILISATION DE 5-CARBOXYMÉTHYL-3-MERCAPTO-1,2,4-TRIAZINO-[5,6-B]INDOLES ET LEUR COMPOSITION PHARMACEUTIQUE
  申请人：STAV EXPERIMENTÁLNEJ FARMAKOLÓGIE A TOXIKOLÓGIE SAV

  公开号：WO2015057175A1

  公开（公告）日：2015-04-23

  The present invention relates to the use of 5-carboxymethyl-3- mercapto-1,2,4-triazino-[5,6-b]indoles (the general formula (I)) and their pharmaceutically acceptable salts hydrates and solvates thereof for the use in treatment, control and prevention of human and veterinary diseases in which activities of aldo- keto reductases AKR1B1 and AKR1B10 are key etiological factors for their development and progress such as the development of diabetic complications (macro-, microangiopathy, atherosclerosis, retinopathy, cataracts, nephropathy, neuropathy, bone mass loss and atherosclerosis), inflammatory diseases (uveitis, sepsis, periodontitis, asthma and colorectal cancer), abnormal proliferation of vascular smooth muscle cells in atherosclerosis and restenosis, lung carcinoma in smokers, and several types of cancer (lung, breast, hepatic, prostate, pancreatic, endometrial cancer, cervical cancer, and cervical adenocarcinoma), diseases of the female reproductive system (menstrual disorders and fertility problems), timing of parturition, mood disorders, psychiatric and neurological diseases. The present invention relates to pharmaceutical compositions comprising effective amount of 5-carboxymethyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles of the general formula (I) and a pharmaceutically acceptable carrier for the use in treatment, control and prevention of human and veterinary diseases. (Formula (I))
• [EN] CEMTIRESTAT DISULFIDE, PRODRUG OF ALDO-KETO REDUCTASE INHIBITOR, PREPARATION, PHARMACEUTICAL COMPOSITION AND USE THEREOF<br/>[FR] DISULFURE DE CEMTIRESTAT, PROMÉDICAMENT D'INHIBITEUR D'ALDO-CÉTO RÉDUCTASE, PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION DE CELUI-CI
  申请人：[en]CENTRUM EXPERIMENTÁLNEJ MEDICÍNY SAV

  公开号：WO2022132058A1

  公开（公告）日：2022-06-23

  The present invention relates to a novel prodrug of aldo-keto reductase inhibitor II based on its disulfide (system name "disulfane") of formula I, to a process of the preparation of disulfide of formula I, to the use of disulfide of formula I to inhibit the aldo-keto reductases AKR1B1 and AKR1B10, to the use of disulfide of formula I in the prevention or treatment of diseases in which the activity of the aldo-keto reductases AKR1B1 and AKR1B10 is a key etiological factor for their formation and development, the use of disulfide of formula I for the prevention or treatment of cancer originating from chronic inflammation, namely cancer of colon, lung, breast, liver, prostate, pancreas, endometrial and cervix. The invention also relates to the use of disulfide of formula I for the treatment of cancer as an adjuvant therapeutic in combination with clinically used chemotherapeutics, which may also be a substrate for aldo-keto reductases such as doxorubicin and daunorubicin. Disulfide of formula I itself is inactive as an inhibitor of aldo-keto reductases AKR1B1 and AKR1B10, but after oral or parenteral administration it is metabolized in the body, preferably in cancer cells characterized by increased reduction potential due to GSH content markedly increased compared to healthy cells, producing two molecules of cemtirestat of formula II the active inhibitor of aldo-keto reductase. The disulfide of formula I according to the invention may also have the advantage that it is better absorbed in the acidic environment of the tumors than cemtirestat of formula II alone. Disulfide of formula I can be used alone or in the form of pharmaceutically acceptable forms: a mono- or dibasic salt, mono- or diesters, amides, or combinations thereof or other pharmaceutical agents, optionally in combination with other anti-inflammatory or anti- cancer therapeutics. (I)