6-[(S)-4-(4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile | 1057677-80-1

• 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: 6-[(S)-4-(4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile
• 英文别名: 6-[(2S)-4-(4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile
• CAS: 1057677-80-1
• 化学式: C₂₆H₂₄N₆
• 分子量: 420.517
• InChiKey: ISXNBYFYHJAITP-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 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 6-[(S)-4-(4-benzylphthalazin-1-yl)-2-methylpiperazin-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

• 1-Amino-4-benzylphthalazines as Orally Bioavailable Smoothened Antagonists with Antitumor Activity
  作者：Karen Miller-Moslin、Stefan Peukert、Rishi K. Jain、Michael A. McEwan、Rajesh Karki、Luis Llamas、Naeem Yusuff、Feng He、Yanhong Li、Yingchuan Sun、Miao Dai、Lawrence Perez、Walter Michael、Tao Sheng、Huangshu Lei、Rui Zhang、Juliet Williams、Aaron Bourret、Arun Ramamurthy、Jing Yuan、Ribo Guo、Melissa Matsumoto、Anthony Vattay、Wieslawa Maniara、Adam Amaral、Marion Dorsch、Joseph F. Kelleher

  DOI：10.1021/jm900309j

  日期：2009.7.9

  Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the

  Hedgehog（Hh）信号传导途径的异常激活与几种类型的人类癌症有关，并且该途径的小分子抑制剂的发展代表了一种通往新型抗癌疗法的有前途的途径。在我们实验室中进行的基于细胞的筛选确定了新型的Hh通路抑制剂1-氨基-4-苄基酞嗪，它们通过对平滑受体的拮抗作用发挥作用。合成了多种类似物，并确定了它们的构效关系。这种优化导致发现了高亲和力的平滑化拮抗剂，其中一种在体内得到了进一步的分析。该化合物在神经母细胞瘤的遗传小鼠模型中显示出良好的药代动力学特征，并且还可以使肿瘤消退。
• Organic Compounds and Their Uses
  申请人：Dai Miao

  公开号：US20100069368A1

  公开（公告）日：2010-03-18

  The present disclosure relates to compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders; specifically relating to compounds of formula I:

  本公开涉及与Hedgehog通路相关的病理诊断和治疗相关化合物，包括但不限于肿瘤形成、癌症、肿瘤新生和非恶性增生性疾病；具体涉及式I的化合物。
• Benzyl and pyridinyl derivatives as modulators of the hedgehog signaling pathway
  申请人：Dai Miao

  公开号：US08536168B2

  公开（公告）日：2013-09-17

  The present disclosure relates to compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders; specifically relating to compounds of formula I:

  本公开涉及与Hedgehog通路相关的病理诊断和治疗相关的化合物，包括但不限于肿瘤形成、癌症、肿瘤新生和非恶性增生性疾病；具体涉及公式I的化合物。
• ORGANIC COMPOUNDS AND THEIR USES
  申请人：Novartis AG

  公开号：EP2137162B1

  公开（公告）日：2018-08-01
• US8536168B2
  申请人：——

  公开号：US8536168B2

  公开（公告）日：2013-09-17