1-{5-[4-(α-D-mannopyranosyloxy)phenyl]thiophen-3-yl}urea | 1373346-92-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-{5-[4-(α-D-mannopyranosyloxy)phenyl]thiophen-3-yl}urea
• 英文别名: [5-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]-3-thienyl]urea；[5-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]thiophen-3-yl]urea
• CAS: 1373346-92-9
• 化学式: C₁₇H₂₀N₂O₇S
• 分子量: 396.421
• InChiKey: NAYJTZVNVKVDKP-VMMWWAARSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  183
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  C₅H₂BrNOS 在 四(三苯基膦)钯 、 氨 、 sodium methylate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 1.5h， 生成 1-{5-[4-(α-D-mannopyranosyloxy)phenyl]thiophen-3-yl}urea
  参考文献：
  名称：

  Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides

  摘要：

  Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections.

  DOI：

  10.1021/jm300165m

文献信息

• Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides
  作者：Zhenfu Han、Jerome S. Pinkner、Bradley Ford、Erik Chorell、Jan M. Crowley、Corinne K. Cusumano、Scott Campbell、Jeffrey P. Henderson、Scott J. Hultgren、James W. Janetka

  DOI：10.1021/jm300165m

  日期：2012.4.26

  Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections.