N3,N5,3'-三甲基-4'-(((2R,3S,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-3,5-二甲酰胺 | 1373346-85-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: N3,N5,3'-三甲基-4'-(((2R,3S,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-3,5-二甲酰胺
• 英文名称: 4'-(α-D-mannopyranosyloxy)-N,N',3'-trimethylbiphenyl-3,5-dicarboxamide
• 英文别名: N1,N3-dimethyl-5-[3-methyl-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-phenyl]benzene-1,3-dicarboxamide；5-[4-[(2~{r},3~{s},4~{s},5~{s},6~{r})-6-(Hydroxymethyl)-3,4,5-Tris(Oxidanyl)oxan-2-Yl]oxy-3-Methyl-Phenyl]-~{n}1,~{n}3-Dimethyl-Benzene-1,3-Dicarboxamide；1-N,3-N-dimethyl-5-[3-methyl-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzene-1,3-dicarboxamide
• CAS: 1373346-85-0
• 化学式: C₂₃H₂₈N₂O₈
• 分子量: 460.484
• InChiKey: CPNXCPWXQQMNFG-WCZGSDDISA-N

物化性质

• 沸点：
  733.6±60.0 °C(Predicted)
• 密度：
  1.359±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  158
• 氢给体数：
  6
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为产物：
  描述：

  5-溴-N,N-二甲基间苯二甲酰胺 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 sodium methylate 、 potassium acetate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 二甲基亚砜 为溶剂， 反应 6.0h， 生成 N3,N5,3'-三甲基-4'-(((2R,3S,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-3,5-二甲酰胺
  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

• COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
  申请人：Janetka James W.

  公开号：US20120309701A1

  公开（公告）日：2012-12-06

  The present invention encompasses compounds and methods for treating urinary tract infections.

  本发明涵盖了治疗尿路感染的化合物和方法。
• Compounds and methods for treating bacterial infections
  申请人：Washington University

  公开号：US10273260B2

  公开（公告）日：2019-04-30

  The present invention encompasses compounds and methods for treating urinary tract infections.

  本发明包括治疗尿路感染的化合物和方法。
• MANNOSIDE COMPOUNDS AND METHODS OF USE THEREOF
  申请人：The Washington University

  公开号：EP2672820B1

  公开（公告）日：2019-04-17
• US8937167B2
  申请人：——

  公开号：US8937167B2

  公开（公告）日：2015-01-20
• 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.