(E)-5-methoxy-3-(2-(pyridin-3-yl)vinyl)-1H-indole | 1316694-80-0

• 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: (E)-5-methoxy-3-(2-(pyridin-3-yl)vinyl)-1H-indole
• 英文别名: 5-methoxy-3-[(E)-2-pyridin-3-ylethenyl]-1H-indole
• CAS: 1316694-80-0
• 化学式: C₁₆H₁₄N₂O
• 分子量: 250.3
• InChiKey: KLIFPFJAHHTMDY-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  19
• 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：
  37.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  5-甲氧基吲哚-3-甲醛 、 吡啶-3-乙酸盐酸盐 在 三乙胺 、 哌啶 作用下， 以 1,4-二氧六环 为溶剂， 反应 48.17h， 以95%的产率得到(E)-5-methoxy-3-(2-(pyridin-3-yl)vinyl)-1H-indole
  参考文献：
  名称：

  Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

  摘要：

  Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure- activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K-i = 5.5 mu M), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

  DOI：

  10.1021/jm2006782

文献信息

• A privileged dual action Alzheimer's disease therapeutic platform targeting immunopathic and proteopathic mechanisms: (<i>E</i>)-3-styrylindoles as inhibitors of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism and β-amyloid aggregation
  作者：Brendan J. Kelly、Elena Diez-Cecilia、Luzhe Pan、Braden Sweeting、Laura Villar、Alexander Kreft、Mayuri Gupta、Shea L. Johnson、Donald F. Weaver

  DOI：10.1139/cjc-2021-0324

  日期：2022.9.1

  The design of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors targeting immunopathic neuroinflammation has emerged as an area of interest for the treatment of Alzheimer's disease (AD); additionally, recent findings on the clinical benefits of antibodies preventing β-amyloid (Aβ) aggregation have renewed efforts to discover small molecule anti-aggregants targeting proteopathic protein misfolding. Exploiting an endogenous tryptophan-like scaffold, we describe the design and synthesis of small-molecule inhibitors of both immunopathic and proteopathic processes, thus presenting the possibility of single therapeutics acting simultaneously on multiple AD pathogeneses. Specifically, investigations on compounds that inhibit both IDO1 (in human recombinant enzyme, transfected HEK293 cells, and interferon-γ stimulated human microglia assays) and Aβ aggregation (in thioflavin-T and biotinylated-Aβ oligomeric assays) are presented. Five compounds have been identified with high potency against both targets, identifying ( E)-3-styryl indoles as useful tool compounds for developing Alzheimer's therapeutics. Brain penetration of these compounds via passive diffusion or active transport was predicted using Blood-Brain Barrier Score and Brain Exposure Efficiency Score calculations, respectively; the effects of efflux (pgp, BCRP), and influx (OCT1, OCT2) transporters were similarly predicted. Structure–activity relationships were rationalised with molecular docking and molecular dynamics simulations, which also provide insights for future lead compound optimisation.

  针对免疫病理性神经炎症，设计强效吲哚酮 2,3-双加氧酶 1 (IDO1) 酶抑制剂，已成为治疗阿尔茨海默病 (AD) 的研究兴趣领域；此外，最近关于抗体预防β-淀粉样蛋白 (Aβ) 聚集的临床益处的发现，重新激发了发现小分子抗聚集物质靶向蛋白质异常折叠的努力。利用内源性色氨酸样支架，我们描述了小分子抑制剂的设计和合成，可同时作用于免疫病理和蛋白质病理进程，从而提供了单一治疗同时作用于多种AD病因学的可能性。具体而言，介绍了抑制IDO1 (在人重组酶、转染HEK293细胞和干扰素-γ刺激的人类小胶质细胞实验中) 和Aβ聚集 (在硫酸亚油酰胺-T和生物素化-Aβ寡聚物实验中) 的化合物的研究。已经确定了五种对两种靶点具有高效抑制作用的化合物，确定了(E)-3-苯乙烯基吲哚作为开发阿尔茨海默病治疗药物的有用工具化合物。预测了这些化合物通过被动扩散或主动转运的血脑屏障分数和脑暴露效率分数计算的脑穿透性，类似地预测了外流 (pgp、BCRP) 和内流 (OCT1、OCT2) 转运体的影响。通过分子对接和分子动力学模拟对结构活性关系进行了合理化解释，同时为未来的前导化合物优化提供了见解。
• [EN] USE OF DERIVATIVES OF INDOLES FOR THE TREATMENT OF CANCER<br/>[FR] UTILISATION DE DÉRIVÉS D’INDOLES DANS LE TRAITEMENT DU CANCER
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2010150211A2

  公开（公告）日：2010-12-29

  The present invention relates to the use of derivatives of indoles having a general formula (I) as follow: for the manufacture of a pharmaceutical composition intended for the treatment of cancer.
• Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators
  作者：Eduard Dolušić、Pierre Larrieu、Laurence Moineaux、Vincent Stroobant、Luc Pilotte、Didier Colau、Lionel Pochet、Benoît Van den Eynde、Bernard Masereel、Johan Wouters、Raphaël Frédérick

  DOI：10.1021/jm2006782

  日期：2011.8.11

  Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure- activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K-i = 5.5 mu M), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.