4'-(α-D-mannopyranosyloxy)-biphenyl-4-carboxylic acid | 1259474-47-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4'-(α-D-mannopyranosyloxy)-biphenyl-4-carboxylic acid
• 英文别名: 4'-(alpha-D-Mannopyranosyloxy)-biphenyl-4-carboxylic acid；4-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoic acid
• CAS: 1259474-47-9
• 化学式: C₁₉H₂₀O₈
• 分子量: 376.363
• InChiKey: ZLNPXKSDQKJSIZ-GJGATLCTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  27
• 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'-(α-D-mannopyranosyloxy)-biphenyl-4-carboxylic acid 在 吡啶 、 4-二甲氨基吡啶 、 1-氯-N,N,2-三甲基丙烯胺 、 sodium methylate 、 sodium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 4.0h， 生成 N-cyano-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：

  p-bromophenyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside 在 tris-(dibenzylideneacetone)dipalladium(0) 2-双环己基膦-2',6'-二甲氧基联苯 、 sodium methylate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 109.0h， 生成 4'-(α-D-mannopyranosyloxy)-biphenyl-4-carboxylic acid
  参考文献：
  名称：

  [EN] MANNOSE DERIVATIVES AS ANTAGONISTS OF BACTERIAL ADHESION
  [FR] DÉRIVÉS DE MANNOSE UTILISÉS EN TANT QU'ANTAGONISTES DE L'ADHÉSION BACTÉRIENNE

  摘要：

  公开号：

  WO2011073112A3

文献信息

• MANNOSE DERIVATIVES AS ANTAGONISTS OF BACTERIAL ADHESION
  申请人：Ernst Beat

  公开号：US20120270824A1

  公开（公告）日：2012-10-25

  Compounds of the formula (I) wherein n is 0, 1 or 2, R 1 is aryl, heteroaryl or heterocyclyl, and R 2 and R 3 are hydrogen or a substituent as described in the specification, are useful for the prevention and treatment of bacterial infections, in particular of urinary infections caused by E. coli .

  式(I)的化合物，其中n为0、1或2，R1为芳基、杂芳基或杂环基，R2和R3为氢或规范中所述的取代基，对于预防和治疗细菌感染，特别是由大肠杆菌引起的尿路感染是有用的。
• Mannose derivatives as antagonists of bacterial adhesion
  申请人：University of Basel

  公开号：EP2604619A2

  公开（公告）日：2013-06-19

  Compounds of the formula (I) wherein n is 0, 1 or 2, R1 is aryl, heteroaryl or heterocyclyl, and R2 and R3 are hydrogen or a substituent as described in the specification, are useful for the prevention and treatment of bacterial infections, in particular of urinary infections caused by E. coli.

  式 (I) 的化合物 其中 n 为 0、1 或 2，R1 为芳基、杂芳基或杂环基，R2 和 R3 为氢或说明书中所述的取代基，可用于预防和治疗细菌感染，特别是由大肠杆菌引起的泌尿系统感染。
• PHENYL-ALPHA-D-MANNOSIDES FOR USE IN THE TREATMENT OF BACTERIAL INFECTIONS CAUSED BY ESCHERICHIA COLI
  申请人：University of Basel

  公开号：EP2960247A1

  公开（公告）日：2015-12-30

  Compounds of the formula (I) wherein n is 0, 1 or 2, R2 and R3 are hydrogen or a substituent as described in the specification, are useful for the prevention and treatment of bacterial infections, in particular of urinary infections caused by E. coli, wherein R1 is one of groups (B), (C), (D), (E) below:

  式（I）化合物，其中 n 为 0、1 或 2，R2 和 R3 为氢或说明书中所述的取代基，可用于预防和治疗细菌感染，特别是由大肠杆菌引起的泌尿系统感染、 其中 R1 为以下 (B)、(C)、(D)、(E) 组之一：
• [EN] MANNOSE DERIVATIVES AS ANTAGONISTS OF BACTERIAL ADHESION<br/>[FR] DÉRIVÉS DE MANNOSE UTILISÉS EN TANT QU'ANTAGONISTES DE L'ADHÉSION BACTÉRIENNE
  申请人：UNIV BASEL

  公开号：WO2011073112A3

  公开（公告）日：2011-09-09
• 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.