3-(1H-indol-3-yl)-4-[3-(4-methylpiperazin-1-yl)naphthalen-1-yl]pyrrole-2,5-dione | 425636-91-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 3-(1H-indol-3-yl)-4-[3-(4-methylpiperazin-1-yl)naphthalen-1-yl]pyrrole-2,5-dione
• 英文别名: Maleimide derivative, 12
• CAS: 425636-91-5
• 化学式: C₂₇H₂₄N₄O₂
• 分子量: 436.513
• InChiKey: IDSZLHFEKAUIOL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  68.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(1H-indol-3-yl)-4-[3-(4-methylpiperazin-1-yl)naphthalen-1-yl]pyrrole-2,5-dione 、 溶剂黄146 以 甲醇 为溶剂， 以66%的产率得到3-(1H-indol-3-yl)-4-[3-(4-methylpiperazin-1-yl)naphthalen-1-yl]pyrrole-2,5-dione acetate
  参考文献：
  名称：

  Structure–Activity Relationship and Pharmacokinetic Studies of Sotrastaurin (AEB071), a Promising Novel Medicine for Prevention of Graft Rejection and Treatment of Psoriasis

  摘要：

  Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure - activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.

  DOI：

  10.1021/jm200469u
• 作为产物：
  描述：

  (3-trifluoromethanesulfonyloxynaphthalen-1-yl)acetic acid ethyl ester 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium tert-butylate 、 sodium methylate 、 silica gel 、 formamide 、 2-(二叔丁基膦)联苯 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 3-(1H-indol-3-yl)-4-[3-(4-methylpiperazin-1-yl)naphthalen-1-yl]pyrrole-2,5-dione
  参考文献：
  名称：

  Structure–Activity Relationship and Pharmacokinetic Studies of Sotrastaurin (AEB071), a Promising Novel Medicine for Prevention of Graft Rejection and Treatment of Psoriasis

  摘要：

  Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure - activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.

  DOI：

  10.1021/jm200469u

文献信息

• Discovery of 3-(1<i>H</i>-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a Potent and Selective Inhibitor of Protein Kinase C Isotypes
  作者：Jürgen Wagner、Peter von Matt、Richard Sedrani、Rainer Albert、Nigel Cooke、Claus Ehrhardt、Martin Geiser、Gabriele Rummel、Wilhelm Stark、Andre Strauss、Sandra W. Cowan-Jacob、Christian Beerli、Gisbert Weckbecker、Jean-Pierre Evenou、Gerhard Zenke、Sylvain Cottens

  DOI：10.1021/jm901108b

  日期：2009.10.22

  A series of novel maleimide-based inhibitors of protein kinase C (PKC) were designed, synthesized, and evaluated. AEB071 (1) was found to be a potent, selective inhibitor of classical and novel PKC isotypes. 1 is a highly efficient immunomodulator, acting via inhibition of early T cell activation. The binding mode of maleimides to PKCs, proposed by molecular modeling, was confirmed by X-ray analysis

  设计，合成和评估了一系列新型的基于马来酰亚胺的蛋白激酶C（PKC）抑制剂。发现AEB071（1）是经典和新型PKC同种型的有效选择性抑制剂。图1是高效的免疫调节剂，其通过抑制早期T细胞活化而起作用。通过分子建模提出的马来酰亚胺与PKCs的结合模式，通过对PKCα活性位点中结合的1个X射线分析进行了证实。
• IMMUNOGENIC COMPOSITIONS AND USES THEREFOR
  申请人：Epiaxis Therapeutics Pty Ltd

  公开号：US20200282010A1

  公开（公告）日：2020-09-10

  The present invention discloses the use of protein kinase C (PKC-θ) inhibitors for enhancing the immune effector function of functionally repressed T-cells that have undergone epithelial to mesenchymal transition (EMT). In specific embodiments, PKC-θ inhibitors are disclosed for use in enhancing susceptibility of exhausted T-cells to reinvigoration by PD-1 binding antagonists. The compositions of the present invention find utility in treating a range of disorders including T-cell dysfunctional disorders such as pathogenic infections and hyperproliferative disorders.