cyclopropanecarboxylic acid[3-(3-ethyl-ureido)-5-(2-methyl-pyridin-4-yl)-isoquinolin-8-ylmethyl]-amide | 1401309-70-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: cyclopropanecarboxylic acid[3-(3-ethyl-ureido)-5-(2-methyl-pyridin-4-yl)-isoquinolin-8-ylmethyl]-amide
• 英文别名: cyclopropanecarboxylic acid [3-(3-ethyl-ureido)-5-(2-methyl-pyridin-4-yl)-isoquinolin-8-ylmethyl]-amide；N-[[3-(ethylcarbamoylamino)-5-(2-methylpyridin-4-yl)isoquinolin-8-yl]methyl]cyclopropanecarboxamide
• CAS: 1401309-70-3
• 化学式: C₂₃H₂₅N₅O₂
• 分子量: 403.484
• InChiKey: MJNSPZPJHGYCTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  96
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-chloro-3-(3-ethyl-ureido)-isoquinoline-8-carboxylic acid methyl ester 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium aluminium tetrahydride 、 叠氮磷酸二苯酯 、 1-丙基磷酸酐 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 、 三环己基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.5h， 生成 cyclopropanecarboxylic acid[3-(3-ethyl-ureido)-5-(2-methyl-pyridin-4-yl)-isoquinolin-8-ylmethyl]-amide
  参考文献：
  名称：

  Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents

  摘要：

  Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

  DOI：

  10.1021/acs.jmedchem.6b01834

文献信息

• Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents
  作者：Philippe Panchaud、Thierry Bruyère、Anne-Catherine Blumstein、Daniel Bur、Alain Chambovey、Eric A. Ertel、Markus Gude、Christian Hubschwerlen、Loïc Jacob、Thierry Kimmerlin、Thomas Pfeifer、Lars Prade、Peter Seiler、Daniel Ritz、Georg Rueedi

  DOI：10.1021/acs.jmedchem.6b01834

  日期：2017.5.11

  Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.