3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile | 1352609-67-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并吡啶类
• 英文名称: 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile
• 英文别名: 3-[[5-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-imidazol-2-yl]methylamino]-4-(pyrrolidin-1-ylmethyl)benzonitrile
• CAS: 1352609-67-6
• 化学式: C₂₈H₂₇N₉
• 分子量: 489.583
• InChiKey: WKDQUOATEFNKLP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-(2-(dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine 在 盐酸 、 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 、 水 、 1,2-二氯乙烷 为溶剂， 反应 9.0h， 生成 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile
  参考文献：
  名称：

  Discovery of N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent

  摘要：

  A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyriclin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-beta type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALKS with IC50 value of 0.013 mu M in a kinase assay and with IC50 values of 0.0165 and 0.0121 mu M in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALKS/ALK4 inhibitor. Pharmacokinetic study with 12b center dot HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng x h/mL and maximum plasma concentration (C-max) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.

  DOI：

  10.1021/jm500115w

文献信息

• 2-PYRIDYL SUBSTITUTED IMIDAZOLES AS THERAPEUTIC ALK5 AND/OR ALK4 INHIBITORS
  申请人：Kim Dae-Kee

  公开号：US20110319406A1

  公开（公告）日：2011-12-29

  This invention relates to 2-pyridyl substituted imidazoles which are inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and/or the activin type I receptor (ALK4), methods for their preparation, and their use in medicine, specifically in the treatment and prevention of a disease state mediated by these receptors.

  本发明涉及2-吡啶基取代咪唑类化合物，其为转化生长因子-β（TGF-β）类型I受体（ALK5）和/或激活素类型I受体（ALK4）的抑制剂，以及其制备方法和在医学上的应用，特别是用于治疗和预防由这些受体介导的疾病状态。
• 2-Pyridyl substituted imidazoles as therapeutic Alk5 and/or Alk4 inhibitors
  申请人：Ewha University-Industry Collaboration Foundation

  公开号：EP2947081A1

  公开（公告）日：2015-11-25

  This invention relates to 2-pyridyl substituted imidazoles (I) which are inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and/or the activin type I receptor (ALK4), methods for their preparation, and their use in medicine, specifically in the treatment and prevention of a disease state mediated by these receptors.

  本发明涉及作为转化生长因子-β（TGF-β）Ⅰ型受体（ALK5）和/或激活素Ⅰ型受体（ALK4）抑制剂的 2-吡啶基取代的咪唑（I）、其制备方法及其在医学中的用途，特别是在治疗和预防由这些受体介导的疾病状态中的用途。
• Discovery of <i>N</i>-((4-([1,2,4]Triazolo[1,5-<i>a</i>]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1<i>H</i>-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent
  作者：Cheng Hua Jin、Maddeboina Krishnaiah、Domalapally Sreenu、Vura B. Subrahmanyam、Kota S. Rao、Hwa Jeong Lee、So-Jung Park、Hyun-Ju Park、Kiho Lee、Yhun Yhong Sheen、Dae-Kee Kim

  DOI：10.1021/jm500115w

  日期：2014.5.22

  A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyriclin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-beta type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALKS with IC50 value of 0.013 mu M in a kinase assay and with IC50 values of 0.0165 and 0.0121 mu M in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALKS/ALK4 inhibitor. Pharmacokinetic study with 12b center dot HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng x h/mL and maximum plasma concentration (C-max) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.
• Methods of Treating Fibrosis, Cancer and Vascular Injuries
  申请人：Kim Dae-Kee

  公开号：US20110319408A1

  公开（公告）日：2011-12-29

  This invention relates to use of inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and/or the activin type I receptor (ALK4) in treating, preventing, or reducing fibrosis, cancer, and vascular injuries.
• US8080568B1
  申请人：——

  公开号：US8080568B1

  公开（公告）日：2011-12-20