3-(3-(4-(methylsulfonyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)benzamide | 1580453-82-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3-(3-(4-(methylsulfonyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)benzamide
• 英文别名: 3-[3-(4-Methylsulfonylphenyl)imidazo[1,2-b]pyridazin-6-yl]benzamide；3-[3-(4-methylsulfonylphenyl)imidazo[1,2-b]pyridazin-6-yl]benzamide
• CAS: 1580453-82-2
• 化学式: C₂₀H₁₆N₄O₃S
• 分子量: 392.438
• InChiKey: WUXTVJVWSNBFOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-氯-3-碘咪唑并[1,2-B]哒嗪 在 bis-triphenylphosphine-palladium(II) chloride 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 3-(3-(4-(methylsulfonyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)benzamide
  参考文献：
  名称：

  Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1

  摘要：

  A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.

  DOI：

  10.1021/jm500098s

文献信息

• Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2
  作者：Claire Le Manach、Tanya Paquet、Diego Gonzàlez Cabrera、Yassir Younis、Dale Taylor、Lubbe Wiesner、Nina Lawrence、Sylva Schwager、David Waterson、Michael J. Witty、Sergio Wittlin、Leslie J. Street、Kelly Chibale

  DOI：10.1021/jm500887k

  日期：2014.11.13

  On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 x 50 mg/kg po.
• Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1
  作者：Claire Le Manach、Diego Gonzàlez Cabrera、Frederic Douelle、Aloysius T. Nchinda、Yassir Younis、Dale Taylor、Lubbe Wiesner、Karen L. White、Eileen Ryan、Corinne March、Sandra Duffy、Vicky M. Avery、David Waterson、Michael J. Witty、Sergio Wittlin、Susan A. Charman、Leslie J. Street、Kelly Chibale

  DOI：10.1021/jm500098s

  日期：2014.3.27

  A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.