6-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-yl]-N-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]pyrido[3,2-d]pyrimidin-4-amine | 1400632-62-3

• 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: 6-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-yl]-N-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]pyrido[3,2-d]pyrimidin-4-amine
• 英文别名: 6-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]pyrido[3,2-d]pyrimidin-4-amine
• CAS: 1400632-62-3
• 化学式: C₂₄H₂₁F₂N₇S
• 分子量: 477.54
• InChiKey: HTUXRAUCKBVRRI-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  99.5
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-氯吡啶并[3,2-d]嘧啶-4(1H)-酮 在 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 4.25h， 生成 6-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-yl]-N-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]pyrido[3,2-d]pyrimidin-4-amine
  参考文献：
  名称：

  Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

  摘要：

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

  DOI：

  10.1021/jm5006429

文献信息

• [EN] TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF<br/>[FR] INHIBITEURS DE KINASE TRKA, COMPOSITIONS ET PROCÉDÉS ASSOCIÉS
  申请人：MERCK SHARP & DOHME

  公开号：WO2012125668A1

  公开（公告）日：2012-09-20

  The present invention is directed to quinazolinyl and pyridoquinazolinyl compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.

  本发明涉及式(I)的喹唑啉基和吡啶喹唑啉基化合物，它们是肌浆蛋白相关激酶（Trk）家族蛋白激酶抑制剂，因此在治疗疼痛、炎症、癌症、再狭窄、动脉粥样硬化、牛皮癣、血栓形成、与脱髓鞘或髓鞘损伤或功能障碍相关的疾病、紊乱、损伤或与神经生长因子（NGF）受体TrkA异常活动相关的疾病或紊乱的治疗中有用。
• Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain
  作者：Shawn J. Stachel、John M. Sanders、Darrell A. Henze、Mike T. Rudd、Hua-Poo Su、Yiwei Li、Kausik K. Nanda、Melissa S. Egbertson、Peter J. Manley、Kristen L. G. Jones、Edward J. Brnardic、Ahren Green、Jay A. Grobler、Barbara Hanney、Michael Leitl、Ming-Tain Lai、Vandna Munshi、Dennis Murphy、Keith Rickert、Daniel Riley、Alicja Krasowska-Zoladek、Christopher Daley、Paul Zuck、Stephanie A. Kane、Mark T. Bilodeau

  DOI：10.1021/jm5006429

  日期：2014.7.10

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.