N-[2-(6-methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]pyridin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并三嗪类
• 英文名称: N-[2-(6-methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]pyridin-4-amine
• 英文别名: US10336761, Example 49；2-(6-methylpyridin-2-yl)-N-pyridin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine
• 化学式: C₁₇H₁₄N₆
• 分子量: 302.338
• InChiKey: BYPWTZRGWLOOAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-氨基吡啶 、 2-(6-methylpyridin-2-yl)-4-phenoxypyrrolo[2,1-f][1,2,4]triazine 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 1.0h， 以52%的产率得到N-[2-(6-methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]pyridin-4-amine
  参考文献：
  名称：

  Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFβRI)

  摘要：

  The TGF beta-TGF beta R signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGF beta R has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGF beta RI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T-1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGF beta-stimulated phospho-SMAD was observed in primary human T cells. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.01.014

文献信息

• [EN] TGF BETA RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DES RÉCEPTEURS TGF BÊTA
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2017015425A1

  公开（公告）日：2017-01-26

  The invention relates generally to compounds that modulate the activity of TGFβR-1 and TGFβ R-2, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.

  这项发明涉及一般调节TGFβR-1和TGFβR-2活性的化合物，包含这些化合物的药物组合物以及利用该发明的化合物治疗增殖性疾病和失调凋亡疾病（如癌症）的方法。
• TGFβ receptor antagonist
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10336761B2

  公开（公告）日：2019-07-02

  The invention relates generally to compounds that modulate the activity of TGFβR-1 and TGFβ R-2, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.

  本发明一般涉及调节 TGFβR-1 和 TGFβ R-2 活性的化合物、含有上述化合物的药物组合物以及利用本发明化合物治疗增殖性疾病和凋亡失调疾病（如癌症）的方法。
• TGF BETA RECEPTOR ANTAGONISTS
  申请人：Bristol-Myers Squibb Company

  公开号：US20180215761A1

  公开（公告）日：2018-08-02

  The invention relates generally to compounds that modulate the activity of TGFβR-1 and TGFβ R-2, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.
• Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFβRI)
  作者：Lalgudi S. Harikrishnan、Jayakumar Warrier、Andrew J. Tebben、Gopikishan Tonukunuru、Sudhakara R. Madduri、Vishweshwaraiah Baligar、Raju Mannoori、Balaji Seshadri、Hasibur Rahaman、P.N. Arunachalam、Amol G. Dikundwar、Brian E. Fink、Joseph Fargnoli、Mark Fereshteh、Yi Fan、Jonathan Lippy、Ching-Ping Ho、Barri Wautlet、Steven Sheriff、Max Ruzanov、Robert M. Borzilleri

  DOI：10.1016/j.bmc.2018.01.014

  日期：2018.3

  The TGF beta-TGF beta R signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGF beta R has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGF beta RI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T-1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGF beta-stimulated phospho-SMAD was observed in primary human T cells. (C) 2018 Elsevier Ltd. All rights reserved.