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。