N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3'-chloro-4'-(α-D-mannopyranosyloxy)biphenyl-4-carboxamide | 1577169-67-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3'-chloro-4'-(α-D-mannopyranosyloxy)biphenyl-4-carboxamide
• 英文别名: N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[3-chloro-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzamide
• CAS: 1577169-67-5
• 化学式: C₂₅H₃₃ClN₂O₉
• 分子量: 540.998
• InChiKey: NEEDDFAKFQKJAO-BZDYCCQFSA-N

物化性质

• 沸点：
  799.6±60.0 °C(predicted)
• 密度：
  1.376±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  37
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  173
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  6-异硫氰酸荧光素 、 N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3'-chloro-4'-(α-D-mannopyranosyloxy)biphenyl-4-carboxamide 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以65%的产率得到3'-chloro-N-(2-(2-(2-(3-(3',6'-dihydroxy-3-oxo-3H-spiro-[isobenzofuran-1,9'-xanthen]-5-yl)thioureido)ethoxy)ethoxy)-ethyl)-4'-(α-D-mannopyranosyloxy)biphenyl-4-carboxamide
  参考文献：
  名称：

  FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile

  摘要：

  Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl a-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(a-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.

  DOI：

  10.1021/jm501524q
• 作为产物：
  描述：

  2-(2-(2-氨基乙氧基)乙氧基)乙基氨基甲酸叔丁酯 在 N-羟基丁二酰亚胺 、 三氟乙酸 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3'-chloro-4'-(α-D-mannopyranosyloxy)biphenyl-4-carboxamide
  参考文献：
  名称：

  FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile

  摘要：

  Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl a-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(a-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.

  DOI：

  10.1021/jm501524q

文献信息

• Kinetic Properties of Carbohydrate-Lectin Interactions: FimH Antagonists
  作者：Meike Scharenberg、Xiaohua Jiang、Lijuan Pang、Giulio Navarra、Said Rabbani、Florian Binder、Oliver Schwardt、Beat Ernst

  DOI：10.1002/cmdc.201300349

  日期：2014.1

  part of the preclinical development process, when the kinetic properties of FimH antagonists were examined by surface plasmon resonance, extremely low dissociation rates (koff) were found, which is uncommon for carbohydrate–lectin interactions. As a consequence, the corresponding half‐lives (t1/2) of the FimH antagonist complexes are above 3.6 h. For a therapeutic application, extended t1/2 values are

  凝集素FimH在尿路致病性大肠杆菌（UPEC）的1型菌毛上最终表达，这是尿路感染（UTI）的主要原因。FimH使细菌粘附到尿道上皮细胞，这是感染的第一步。各种甘露糖衍生物已显示出拮抗FimH，因此被认为是用于治疗UTI的有前途的治疗剂。作为临床前开发过程的一部分，当通过表面等离子体激元共振检查FimH拮抗剂的动力学特性时，发现极低的解离速率（k off），这在碳水化合物-凝集素相互作用中并不常见。结果，相应的半衰期（t 1/2）的FimH拮抗剂复合物在3.6 h以上。对于治疗应用而言，扩展的t 1/2值是成功的先决条件，因为目标占用时间直接影响体内药物的功效。经过测试的FimH拮抗剂的t 1/2值长，进一步证实了它们的药物样特性和高治疗潜力。
• FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile
  作者：Simon Kleeb、Lijuan Pang、Katharina Mayer、Deniz Eris、Anja Sigl、Roland C. Preston、Pascal Zihlmann、Timothy Sharpe、Roman P. Jakob、Daniela Abgottspon、Aline S. Hutter、Meike Scharenberg、Xiaohua Jiang、Giulio Navarra、Said Rabbani、Martin Smiesko、Nathalie Lüdin、Jacqueline Bezençon、Oliver Schwardt、Timm Maier、Beat Ernst

  DOI：10.1021/jm501524q

  日期：2015.3.12

  Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl a-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(a-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.