4-(6-(4-(2-methoxyethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(6-(4-(2-methoxyethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide
• 英文别名: 4-[6-[4-(2-methoxyethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide
• 化学式: C₂₂H₁₉F₃N₄O₃S
• 分子量: 476.479
• InChiKey: BBEQRPZTAJPSME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-溴-3-碘-吡唑并[1,5-a]嘧啶 在 四(三苯基膦)钯 、 sodium carbonate 、 caesium carbonate 、 sodium iodide 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-(6-(4-(2-methoxyethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide
  参考文献：
  名称：

  Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties

  摘要：

  Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.02.003

文献信息

• Treatment of Alzheimer's Disease and Related Conditions
  申请人：Churcher Ian

  公开号：US20100240647A1

  公开（公告）日：2010-09-23

  Compounds of formula (I) inhibit microtubule affinity regulating kinase (MARK), and hence are suitable for treating diseases associated with abnormal phosphorylation of tau.

  式(I)的化合物抑制微管亲和力调节激酶（MARK），因此适用于治疗与tau异常磷酸化相关的疾病。
• [EN] TREATMENT OF ALZHEIMER'S DISEASE AND RELATED CONDITIONS<br/>[FR] TRAITEMENT DE LA MALADIE D'ALZHEIMER ET DE CONDITIONS APPARENTÉES
  申请人：MERCK SHARP & DOHME

  公开号：WO2007085873A1

  公开（公告）日：2007-08-02

  [EN] Compounds of formula (I) inhibit microtubule affinity regulating kinase (MARK), and hence are suitable for treating diseases associated with abnormal phosphorylation of tau.
  [FR] Les composés de formule I : inhibent la kinase régulant l'affinité pour les microtubules (MARK, microtubule affinity regulating kinase) et, de ce fait, sont adéquats pour traiter des maladies associées à une phosphorylation anormale de tau.
• Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties
  作者：David L. Sloman、Njamkou Noucti、Michael D. Altman、Dapeng Chen、Andrea C. Mislak、Alexander Szewczak、Mansuo Hayashi、Lee Warren、Tammy Dellovade、Zhenhua Wu、Jacob Marcus、Deborah Walker、Hua-Poo Su、Suzanne C. Edavettal、Sanjeev Munshi、Michael Hutton、Hugh Nuthall、Matthew G. Stanton

  DOI：10.1016/j.bmcl.2016.02.003

  日期：2016.9

  Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility. (C) 2016 Elsevier Ltd. All rights reserved.