(R)-6-(4-(4-benzylphthalazin-1-yl)-2-isopropylpiperazin-1-yl)nicotinonitrile | 1610536-31-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-6-(4-(4-benzylphthalazin-1-yl)-2-isopropylpiperazin-1-yl)nicotinonitrile
• 英文别名: 6-[(2R)-4-(4-benzylphthalazin-1-yl)-2-propan-2-ylpiperazin-1-yl]pyridine-3-carbonitrile
• CAS: 1610536-31-6
• 化学式: C₂₈H₂₈N₆
• 分子量: 448.571
• InChiKey: MFASMRAAELJWJK-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  68.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-氯-3-氰基吡啶 在 tetrakis(actonitrile)copper(I) hexafluorophosphate 、 potassium carbonate 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 46.5h， 生成 (R)-6-(4-(4-benzylphthalazin-1-yl)-2-isopropylpiperazin-1-yl)nicotinonitrile
  参考文献：
  名称：

  Orally Active 7-Substituted (4-Benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as Active-Site Inhibitors of Sphingosine 1-Phosphate Lyase for the Treatment of Multiple Sclerosis

  摘要：

  Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.

  DOI：

  10.1021/jm500338n

文献信息

• Orally Active 7-Substituted (4-Benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as Active-Site Inhibitors of Sphingosine 1-Phosphate Lyase for the Treatment of Multiple Sclerosis
  作者：Sven Weiler、Nadine Braendlin、Christian Beerli、Christian Bergsdorf、Anna Schubart、Honnappa Srinivas、Berndt Oberhauser、Andreas Billich

  DOI：10.1021/jm500338n

  日期：2014.6.26

  Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.