N-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-(phenylsulfanyl)pyrimidin-4-amine | 2231038-82-5

• 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: N-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-(phenylsulfanyl)pyrimidin-4-amine
• 英文别名: N-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-phenylsulfanylpyrimidin-4-amine
• CAS: 2231038-82-5
• 化学式: C₂₄H₂₄FN₇S
• 分子量: 461.566
• InChiKey: NIYBCVRMZHPXIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  98.3
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4,6-dichloro-2-(phenylthio)pyrimidine 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-(phenylsulfanyl)pyrimidin-4-amine
  参考文献：
  名称：

  From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical Candidate

  摘要：

  Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compounds in clinical trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-determining features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compounds based on orthogonal methods grounded in computational chemistry and machine learning. Eighteen high-ranking compounds were synthesized and experimentally tested. The top-ranked compound has 10000-fold improved selectivity versus AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.

  DOI：

  10.1021/acs.jmedchem.8b00140

文献信息

• [EN] PYRIMIDINE DERIVATIVES AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS<br/>[FR] DÉRIVÉS DE PYRIMIDINE UTILISÉS EN TANT QU'INHIBITEURS DU RÉCEPTEUR DE KINASE A LIÉ À LA TROPOMYOSINE (TRKA)
  申请人：BIOMED X GMBH

  公开号：WO2019101843A1

  公开（公告）日：2019-05-31

  The present invention relates to novel TrkA inhibitors ofofmrula (1) which are useful in the treatment or prevention of acute and chronic pain but also for other abnormal activities of TrkA beyond pain therapy, such as inflammation and cancer.

  本发明涉及一种新型TrkA抑制剂，其化学式为（1），该抑制剂可用于治疗或预防急性和慢性疼痛，但也可用于治疗TrkA在疼痛治疗之外的其他异常活动，如炎症和癌症。
• PYRIMIDINE DERIVATIVES AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS
  申请人：BioMed X GmbH

  公开号：EP3672957A1

  公开（公告）日：2020-07-01
• Pyrimidine Derivatives as Tropomyosin Receptor Kinase A (TRKA) Inhibitors
  申请人：BIOMED X GMBH

  公开号：US20200399250A1

  公开（公告）日：2020-12-24

  The present invention relates to novel TrkA inhibitors of formula (1) which are useful in the treatment or prevention of acute and chronic pain but also for other abnormal activities of TrkA beyond pain therapy, such as inflammation and cancer.