(2S,4R)-1-((S)-1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)-amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-15-(tert-butyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide | 2010159-47-2

• 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: (2S,4R)-1-((S)-1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)-amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-15-(tert-butyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
• 英文别名: (2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[[4-[(2S,4R)-1-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide
• CAS: 2010159-47-2
• 化学式: C₅₅H₆₆ClN₇O₉S
• 分子量: 1036.69
• InChiKey: FYSWLIFIYIVHPI-DDWISSAJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  73
• 可旋转键数：
  22
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  229
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  (2S,4R)-1-((S)-14-azido-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 在 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 21.0h， 生成 (2S,4R)-1-((S)-1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)-amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-15-(tert-butyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  目标弹头和连接载体对诱导蛋白质降解的影响：来自三唑二氮卓 (JQ1) 和四氢喹啉 (I-BET726) BET 抑制剂支架的溴结构域和末端 (BET) 降解剂的比较。

  摘要：

  蛋白水解靶向嵌合体 (PROTACs) 的设计是一种用于诱导蛋白质降解的强大小分子方法。PROTAC 通过接头将靶弹头与 E3 泛素连接酶配体结合。在这里，我们检查了通过不同的出口载体，使用不同的聚乙二醇接头与 VHL 配体 VH032 衍生两种不同的 BET 溴结构域抑制剂三唑二氮卓 JQ1 和更有效的四氢喹啉 I-BET726 的影响。三唑二氮杂类PROTACs表现出三元络合物形成的正协同作用，并且比四氢喹啉化合物更有效，而四氢喹啉化合物则表现出负协同作用。在急性髓性白血病细胞系中观察到 BET 降解和 cMyc 驱动的抗增殖活性对接头长度的显着依赖性。这项工作作为一个警示故事举例说明了一个更有效的抑制剂不一定会产生更有效的 PROTAC，并强调了共轭所起的关键作用。为二价降解剂的构效关系提供的见解和框架预计将具有广泛的未来适用性。

  DOI：

  10.1021/acs.jmedchem.6b01912

文献信息

• [EN] DERIVATIVES OF 1-[(CYCLOPENTYL OR 2-PYRROLIDINYL)CARBONYLAMINOMETHYL]-4-(1,3-THIAZOL-5-YL) BENZENE WHICH ARE USEFUL FOR THE TREATMENT OF PROLIFERATIVE, AUTOIMMUNE OR INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS DE 1-[(CYCLOPENTYL OU 2-PYRROLIDINYL)CARBONYLAMINOMÉTHYL]-4-(1,3-THIAZOL-5-YL)-BENZÈNE QUI SONT UTILES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES, AUTO-IMMUNES OU INFLAMMATOIRES
  申请人：UNIV DUNDEE

  公开号：WO2016146985A1

  公开（公告）日：2016-09-22

  There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.

  提供了新型小分子E3泛素连接酶蛋白结合配体化合物，适用于蛋白质降解靶向嵌合物（PROTACs），以及其制备过程和在医学中的用途。特别提供了能够结合到溴-和额外末端（BET）蛋白家族中的蛋白质的PROTACs，尤其是包括新型小分子E3泛素连接酶蛋白结合配体化合物的PROTACs，其选择性诱导BET蛋白家族中溴结构域内的BRD4蛋白降解。
• Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(l,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases
  申请人：University of Dundee

  公开号：US11179373B2

  公开（公告）日：2021-11-23

  There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.

  本发明提供了新型小分子 E3 泛素配体蛋白结合配体化合物，这些化合物可用于 Proteolysis Targeted Chimeras（PROTACs）及其制备工艺和医学用途。特别提供了与溴外端（BET）蛋白家族中的蛋白结合的PROTACs，尤其是包括新型小分子E3泛素配体蛋白结合配体化合物的PROTACs，该化合物可选择性地诱导BET蛋白家族溴域中的BRD4蛋白降解。
• DERIVATIVES OF 1-[(CYCLOPENTYL OR 2-PYRROLIDINYL)CARBONYLAMINOMETHYL]-4-(1,3-THIAZOL-5-YL) BENZENE WHICH ARE USEFUL FOR THE TREATMENT OF PROLIFERATIVE, AUTOIMMUNE OR INFLAMMATORY DISEASES
  申请人：The University of Dundee

  公开号：EP3268363B1

  公开（公告）日：2022-05-04
• Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(1,3-Thiazol-5-yl) benzene which are Useful for the Treatment of Proliferative, Autoimmune or Inflammatory Diseases
  申请人：University of Dundee

  公开号：US20180050021A1

  公开（公告）日：2018-02-22

  There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.
• Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds
  作者：Kwok-Ho Chan、Michael Zengerle、Andrea Testa、Alessio Ciulli

  DOI：10.1021/acs.jmedchem.6b01912

  日期：2018.1.25

  observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders are anticipated to have

  蛋白水解靶向嵌合体 (PROTACs) 的设计是一种用于诱导蛋白质降解的强大小分子方法。PROTAC 通过接头将靶弹头与 E3 泛素连接酶配体结合。在这里，我们检查了通过不同的出口载体，使用不同的聚乙二醇接头与 VHL 配体 VH032 衍生两种不同的 BET 溴结构域抑制剂三唑二氮卓 JQ1 和更有效的四氢喹啉 I-BET726 的影响。三唑二氮杂类PROTACs表现出三元络合物形成的正协同作用，并且比四氢喹啉化合物更有效，而四氢喹啉化合物则表现出负协同作用。在急性髓性白血病细胞系中观察到 BET 降解和 cMyc 驱动的抗增殖活性对接头长度的显着依赖性。这项工作作为一个警示故事举例说明了一个更有效的抑制剂不一定会产生更有效的 PROTAC，并强调了共轭所起的关键作用。为二价降解剂的构效关系提供的见解和框架预计将具有广泛的未来适用性。