4-[(2-氟-4-甲基苯基)氨基]-7-甲氧基-6-[4-(2-甲氧基乙基)哌嗪-1-基]噌啉-3-甲酰胺 | 1041852-77-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 4-[(2-氟-4-甲基苯基)氨基]-7-甲氧基-6-[4-(2-甲氧基乙基)哌嗪-1-基]噌啉-3-甲酰胺
• 英文名称: 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(4-(2-methoxyethyl)piperazin-1-yl)cinnoline-3-carboxamide
• 英文别名: 4-(2-Fluoro-4-methylanilino)-7-methoxy-6-[4-(2-methoxyethyl)piperazin-1-yl]cinnoline-3-carboxamide；4-(2-fluoro-4-methylanilino)-7-methoxy-6-[4-(2-methoxyethyl)piperazin-1-yl]cinnoline-3-carboxamide
• CAS: 1041852-77-0
• 化学式: C₂₄H₂₉FN₆O₃
• 分子量: 468.531
• InChiKey: RCPJYIPGRPCJFQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-[(2-fluoro-4-methylphenyl)amino]-7-methoxy-6-[4-(2-methoxyethyl)piperazin-1-yl]cinnoline-3-carbonitrile 在 potassium hydroxide 作用下， 以 叔丁醇 为溶剂， 生成 4-[(2-氟-4-甲基苯基)氨基]-7-甲氧基-6-[4-(2-甲氧基乙基)哌嗪-1-基]噌啉-3-甲酰胺
  参考文献：
  名称：

  Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

  摘要：

  The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.06.031

文献信息

• SYSTEMS AND METHODS OF SELECTING COMPOUNDS WITH REDUCED RISK OF CARDIOTOXICITY USING CARDIAC SODIUM ION CHANNEL MODELS
  申请人：THE GOVERNORS OF THE UNIVERSITY OF ALBERTA

  公开号：US20180068053A1

  公开（公告）日：2018-03-08

  Provided herein are systems and methods for selecting compounds that have reduced risk of cardiotoxicity or which are not likely to be cardiotoxic. As an example, a system and method can include a computational dynamic model combined with a high throughput screening in silico that mimics an important ion channels associated with cardiotoxicity, namely the human cardiac sodium ion (hNa v 1.5) channel). In certain embodiments, steered molecular dynamics simulations are used to identify key residues of the channel's permeation pathways that are then used in the high throughput screening. Also provided herein are systems and methods for redesigning compounds that are predicted to be cardiotoxic based on the model and the high throughput screening.
• Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507
  作者：David A. Scott、Les A. Dakin、Kevin Daly、David J. Del Valle、R. Bruce Diebold、Lisa Drew、Jayachandran Ezhuthachan、Thomas W. Gero、Claude A. Ogoe、Charles A. Omer、Sean P. Redmond、Galina Repik、Kumar Thakur、Qing Ye、Xiaolan Zheng

  DOI：10.1016/j.bmcl.2013.06.031

  日期：2013.8

  The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507. (C) 2013 Elsevier Ltd. All rights reserved.