(2Z,5Z)-5-{[1-(2,4-Difluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]me thylene}-2-[(2-methoxyethyl)imino]-3-methyl-1,3-thiazolidin-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (2Z,5Z)-5-{[1-(2,4-Difluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]me thylene}-2-[(2-methoxyethyl)imino]-3-methyl-1,3-thiazolidin-4-one
• 英文别名: CYM50308
• CAS: 1345858-76-5
• 化学式: C₂₀H₂₁F₂N₃O₂S
• 分子量: 405.468
• InChiKey: BKQZKTRCUAWRHT-ZGNGNRKCSA-N

物化性质

• 沸点：
  504.0±60.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：1mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.92
• 重原子数：
  28.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  46.83
• 氢给体数：
  0.0
• 氢受体数：
  5.0

制备方法与用途

生物活性

CYM50308（ML248）是一种有效的、选择性和高亲和力的鞘氨醇-1-磷酸受体 4 (S1P4-R) 激动剂，其EC50值为56 nM。相比S1P5-R（EC50值为2100 nM），CYM50308对S1P4-R的选择性高出了37倍。在高达25 μM的浓度下，它对S1P1-R、S1P2-R和S1P3-R均无活性。

靶点

EC50: 56 nM (S1P₄-R), 2100 nM (S1P₅-R)

体外研究

公开的先导分子CYM50308（Compound 24f）展示了低纳摩尔级别的S1P4-R激动剂活性，并且对其他S1P受体亚型表现出极高的选择性。值得注意的是，CYM50308提供了一个宝贵的药理学工具，可用于探索S1P4-R信号级联效应及阐明体内受体功能的分子基础。

反应信息

• 作为产物：
  描述：

  N-(2-methoxyethyl)-N'-methylthiourea 在 哌啶 、 sodium acetate 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 (2Z,5Z)-5-{[1-(2,4-Difluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]me thylene}-2-[(2-methoxyethyl)imino]-3-methyl-1,3-thiazolidin-4-one
  参考文献：
  名称：

  Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype

  摘要：

  High affinity and selective S1P(4) receptor (S1P(4)-R) small molecule agonists may be important proof-of-principle tools used to clarify the receptor biological function and effects to assess the therapeutic potential of the S1P4-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Molecular Libraries-Small Molecule Repository was carried out by our laboratories and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P(4)-R agonist hit distinct from literature S1P(4)-R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P(4)-R agonist activity and exquisite selectivity over the other S1P(1-3,5)-Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P(4)-R signaling cascade and elucidate the molecular basis of the receptor function. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.049

文献信息

• Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype
  作者：Mariangela Urbano、Miguel Guerrero、Subash Velaparthi、Melissa Crisp、Peter Chase、Peter Hodder、Marie-Therese Schaeffer、Steven Brown、Hugh Rosen、Edward Roberts

  DOI：10.1016/j.bmcl.2011.09.049

  日期：2011.11

  High affinity and selective S1P(4) receptor (S1P(4)-R) small molecule agonists may be important proof-of-principle tools used to clarify the receptor biological function and effects to assess the therapeutic potential of the S1P4-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Molecular Libraries-Small Molecule Repository was carried out by our laboratories and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P(4)-R agonist hit distinct from literature S1P(4)-R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P(4)-R agonist activity and exquisite selectivity over the other S1P(1-3,5)-Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P(4)-R signaling cascade and elucidate the molecular basis of the receptor function. (C) 2011 Elsevier Ltd. All rights reserved.