N-(3-fluoropyridin-2-yl)-5-(6-methylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-amine | 1595289-33-0

• 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: N-(3-fluoropyridin-2-yl)-5-(6-methylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-amine
• 英文别名: N-(3-fluoro-2-pyridyl)-5-(6-methylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-amine
• CAS: 1595289-33-0
• 化学式: C₁₆H₁₂FN₇
• 分子量: 321.317
• InChiKey: GIHCWBCPXWYSOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-甲基-3-氨基哒嗪 在 N-溴代丁二酰亚胺(NBS) 、 dichloro bis((p-dimethylaminophenyl)-ϖ-di-tert-butylphosphine)palladium(II) 、 palladium diacetate 、 sodium carbonate 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 水 、 乙腈 、 正丁醇 为溶剂， 反应 12.0h， 生成 N-(3-fluoropyridin-2-yl)-5-(6-methylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-amine
  参考文献：
  名称：

  Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

  摘要：

  A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (Pf CDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.

  DOI：

  10.1021/jm500342d

文献信息

• Optimization of an Imidazopyridazine Series of Inhibitors of <i>Plasmodium falciparum</i> Calcium-Dependent Protein Kinase 1 (<i>Pf</i>CDPK1)
  作者：Timothy M. Chapman、Simon A. Osborne、Claire Wallace、Kristian Birchall、Nathalie Bouloc、Hayley M. Jones、Keith H. Ansell、Debra L. Taylor、Barbara Clough、Judith L. Green、Anthony A. Holder

  DOI：10.1021/jm500342d

  日期：2014.4.24

  A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (Pf CDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.