6-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)nicotinic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)nicotinic acid
• 英文别名: 6-[[2-[6-(trifluoromethyl)pyridin-3-yl]-3H-imidazo[4,5-c]pyridin-6-yl]amino]pyridine-3-carboxylic acid
• 化学式: C₁₈H₁₁F₃N₆O₂
• 分子量: 400.32
• InChiKey: DMVSKJOFHKVIFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  6-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)nicotinic acid 、 环丙胺 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 N-cyclopropyl-6-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)nicotinamide
  参考文献：
  名称：

  Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To Circumvent Atypical Dose–Response Curves against Multidrug Resistant Parasite Strains

  摘要：

  A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2R gamma null mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.8b01333
• 作为产物：
  描述：

  6-氨基烟酸甲酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium hydroxide monohydrate 、 2-(二环己基膦)3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯 、 caesium carbonate 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 水 、 甲苯 、 叔丁醇 为溶剂， 反应 24.0h， 生成 6-((2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)nicotinic acid
  参考文献：
  名称：

  Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To Circumvent Atypical Dose–Response Curves against Multidrug Resistant Parasite Strains

  摘要：

  A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2R gamma null mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.8b01333

文献信息

• Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized <i>Plasmodium falciparum</i> NODscidIL2Rγ^<i>null</i> Mouse Model of Malaria
  作者：Aloysius T. Nchinda、Claire Le Manach、Tanya Paquet、Diego Gonzàlez Cabrera、Kathryn J. Wicht、Christel Brunschwig、Mathew Njoroge、Efrem Abay、Dale Taylor、Nina Lawrence、Sergio Wittlin、María-Belén Jiménez-Díaz、María Santos Martínez、Santiago Ferrer、Iñigo Angulo-Barturen、Maria Jose Lafuente-Monasterio、James Duffy、Jeremy Burrows、Leslie J. Street、Kelly Chibale

  DOI：10.1021/acs.jmedchem.8b00382

  日期：2018.5.10

  Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion

  从全细胞表型筛选针对人类疟疾寄生虫，恶性疟原虫的化学系列的优化导致鉴定了两个有前途的2，6-二取代的咪唑并吡啶化合物43和74。这些化合物显示出对无性血液阶段寄生虫的有效活性，以及​​它们的体外吸收，分布，代谢和排泄（ADME）特性，在Pf SCID小鼠模型中可在48小时内清除疟原虫的体内寄生虫，转化为体内功效的治疗。
• Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To Circumvent Atypical Dose–Response Curves against Multidrug Resistant Parasite Strains
  作者：Claire Le Manach、Tanya Paquet、Kathryn Wicht、Aloysius T. Nchinda、Christel Brunschwig、Mathew Njoroge、Liezl Gibhard、Dale Taylor、Nina Lawrence、Sergio Wittlin、Charles J. Eyermann、Gregory S. Basarab、James Duffy、Paul V. Fish、Leslie J. Street、Kelly Chibale

  DOI：10.1021/acs.jmedchem.8b01333

  日期：2018.10.25

  A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2R gamma null mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.