4-[3-chloro-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoic acid | 1259474-48-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-[3-chloro-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoic acid
• CAS: 1259474-48-0
• 化学式: C₁₉H₁₉ClO₈
• 分子量: 410.808
• InChiKey: GRWYYZUQOKZFOB-GJGATLCTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  137
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-[3-chloro-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoic acid 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 15.5h， 生成 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

文献信息

• 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.