1-ethyl-3-[4-(3-fluoropyridin-2-yl)-6-(1-oxidopyridin-1-ium-3-yl)-1H-benzimidazol-2-yl]urea | 843651-01-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-ethyl-3-[4-(3-fluoropyridin-2-yl)-6-(1-oxidopyridin-1-ium-3-yl)-1H-benzimidazol-2-yl]urea
• CAS: 843651-01-4
• 化学式: C₂₀H₁₇FN₆O₂
• 分子量: 392.392
• InChiKey: XVUMRTMWRZDOQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氯-3-氟吡啶 在 四(三苯基膦)钯 、 甲烷磺酸 、 溴 、 potassium acetate 、 sodium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-ethyl-3-[4-(3-fluoropyridin-2-yl)-6-(1-oxidopyridin-1-ium-3-yl)-1H-benzimidazol-2-yl]urea
  参考文献：
  名称：

  Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy

  摘要：

  A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.022

文献信息

• Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy
  作者：Emanuele Perola、Dean Stamos、Anne-Laure Grillot、Steven Ronkin、Tiansheng Wang、Arnaud LeTiran、Qing Tang、David D. Deininger、Yusheng Liao、Shi-Kai Tian、Joseph E. Drumm、David P. Nicolau、Pamela R. Tessier、Nagraj Mani、Trudy H. Grossman、Paul S. Charifson

  DOI：10.1016/j.bmcl.2014.03.022

  日期：2014.5

  A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models. (C) 2014 Elsevier Ltd. All rights reserved.