(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid | 1365214-67-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid
• 英文别名: (R)-IPMICFP2；6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboxylic acid
• CAS: 1365214-67-0
• 化学式: C₁₇H₁₅FN₄O₂
• 分子量: 326.33
• InChiKey: ZNYLSIQKGGLFAI-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  70.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 生成 (R)-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)methanol
  参考文献：
  名称：

  COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS

  摘要：

  该发明提供了化合物、包含该化合物的药物组合物以及使用该化合物治疗或预防与TRK激酶活性异常或失调相关的疾病或病症的方法。

  公开号：

  US20120065184A1
• 作为产物：
  描述：

  3-FLUOROPHENYLMAGNESIUM BROMIDE 在 盐酸 、 potassium fluoride 、 potassium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 5.75h， 生成 (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid
  参考文献：
  名称：

  A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human

  摘要：

  The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [C-11]-(R)-3([C-11]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [C-11]-(R)-3 readily crosses the bloodbrain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimers disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [C-11]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.

  DOI：

  10.1021/acs.jmedchem.7b00396

文献信息

• Identification of [¹⁸F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging
  作者：Vadim Bernard-Gauthier、Andrew V. Mossine、Anne Mahringer、Arturo Aliaga、Justin J. Bailey、Xia Shao、Jenelle Stauff、Janna Arteaga、Phillip Sherman、Marilyn Grand’Maison、Pierre-Luc Rochon、Björn Wängler、Carmen Wängler、Peter Bartenstein、Alexey Kostikov、David R. Kaplan、Gert Fricker、Pedro Rosa-Neto、Peter J. H. Scott、Ralf Schirrmacher

  DOI：10.1021/acs.jmedchem.7b01607

  日期：2018.2.22

  of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads

  在神经系统疾病和癌症中发现了TrkA / B / C受体和致癌性Trk融合蛋白的表达和功能异常信号的变化。在这里，我们描述了适用于Trk体内成像的第一个18 F标记的优化前导物[ 18 F] TRACK的开发，它可以轻松地由非活化的芳基前体进行放射合成，同时结合了大大降低的P-gp耐受性和改善的大脑与先前的导联相比，具有更高的动力学特性，同时展现出高的目标亲和力和人类kinome选择性。
• IMIDAZO [1, 2]PYRIDAZIN COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS
  申请人：IRM LLC

  公开号：EP2614062A1

  公开（公告）日：2013-07-17
• US8637516B2
  申请人：——

  公开号：US8637516B2

  公开（公告）日：2014-01-28
• [EN] IMIDAZO [1, 2] PYRIDAZIN COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS<br/>[FR] COMPOSÉS ET COMPOSITIONS À TITRE D'INHIBITEURS DE TRK
  申请人：IRM LLC

  公开号：WO2012034091A1

  公开（公告）日：2012-03-15

  The invention provides compounds of formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase activity.