化合物MRS2578 | 711019-86-2

• 物质功能分类: 生物化工 - 抑制剂 - 神经信号通路(Neuronal Signaling)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 化合物MRS2578
• 中文别名: N,N''-1,4-丁烷二基双[N'-(3-异异硫氰基苯基)硫脲；MRS2578抑制剂；1,1'-(丁烷-1,4-二基)双(3-(3-异硫氰酸苯)硫脲)
• 英文名称: 1,4-Di[3-(3-isothiocyanatophenyl)thioureido]butane
• 英文别名: 1-(3-isothiocyanatophenyl)-3-[4-[(3-isothiocyanatophenyl)carbamothioylamino]butyl]thiourea
• CAS: 711019-86-2
• 化学式: C₂₀H₂₀N₆S₄
• 分子量: 472.7
• InChiKey: QOHNRGHTJPFMSL-UHFFFAOYSA-N

物化性质

• 熔点：
  170 - 173°C
• 沸点：
  652.7±65.0 °C(Predicted)
• 密度：
  1.31
• 溶解度：
  二甲基亚砜：~17 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  201
• 氢给体数：
  4
• 氢受体数：
  6

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S26,S36/37/39,S45
• 危险类别码：
  R36/37/38,R42,R20/21/22
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P261,P284,P301+P310+P330,P302+P352+P312,P304+P340+P312,P342+P311
• 危险性描述：
  H301,H312+H332,H315,H319,H334,H335

制备方法与用途

生物活性

生物活性

MRS 2578是一种有效的P2Y6受体抑制剂，IC50为37 nM，对P2Y1、P2Y2、P2Y4和P2Y11受体的作用活性很弱。

靶点

Target	Value
P2Y6	37 nM

体外研究

MRS2578选择性阻断P2Y6受体活性，而不影响P2Y1、P2Y2、P2Y4或P2Y11受体。在1321N1星形细胞瘤细胞中，MRS2578（1 μM）可以完全阻断UDP对TNFα诱导的细胞凋亡的保护作用。在转染有0.25 μg NF-κB启动子报告基因的HMEC-1细胞中，MRS 2578抑制本底的NF-κB活性并具有时间和剂量依赖特性。MRS 2578（10 μM）完全去除了HMEC-1细胞中TNF-α诱导的NF-κB报告基因活性，并可以显著降低TNF-α诱导的促炎基因的表达。在新生大鼠心肌成纤维细胞中，低于316 nM的MRS 2578可以加强ATPγS和UDP的响应，然而高于此浓度后MRS 2578会抑制ATP和UDP诱导的肌醇磷酸（IP）积累。OVA致敏小鼠中MRS2578处理后可以降低支气管对乙酰甲胆碱高反应性；MRS2578完全阻断肺部上皮细胞中UDP诱导的IL-6、KC和IL-8的释放。

体内研究

在脂多糖诱导的C57BL/6小鼠血管炎症模型中，MRS 2578（10 μM）可以降低角质细胞衍生的趋化因子血清蛋白水平。MRS2578（10 μM，气管内）减轻支气管肺泡灌洗液（BALF）嗜酸性粒细胞增多症以及OVA致敏小鼠BALF中IL-5和IL-13的水平，并导致OVA刺激后乙酰甲胆碱的反应能力显著下降。OVA致敏小鼠中MRS2578（10 μM，气管内）抑制屋尘螨引起的过敏性气道炎症并降低BALF中IL-6和KC水平。

文献信息

• Food intake, body weight and glucose metabolism regulation by modulation of P2Y6 receptor signaling
  申请人：Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.

  公开号：EP3002010A1

  公开（公告）日：2016-04-06

  The present invention is related to compound capable of regulating the activity of P2Y purinoceptor 6 signaling pathway, especially to compounds for inhibition of P2Y purinoceptor 6 polypeptide or inactivation, degradation, downregulation or intercalation of a nucleic acid encoding P2Y purinoceptor 6 or downregulation of P2Y purinoceptor 6 signaling pathway for the treatment of diseases related to energy balance as well as carbohydrate metabolism and homeostasis, preferably glucose metabolism and homeostasis. The present is also related to compounds for activation of P2Y purinoceptor 6 polypeptide or upregulation or modification for advanced transcriptional activity of a nucleic acid encoding P2Y purinoceptor 6, upregulation of P2Y purinoceptor 6 signaling pathway for gaining weight or for the treatment of diseases related to energy balance and carbohydrate metabolism and homeostasis. The invention is further related to methods of identifying said compounds suitable for the treatment of diseases related to energy balance and carbohydrate metabolism and homeostasis. The invention is further related to methods of treatment and diagnosis of diseases related to energy balance and carbohydrate metabolism and homeostasis and associated complications.

  本发明涉及能够调节 P2Y 嘌呤受体 6 信号通路活性的化合物，特别是用于抑制 P2Y 嘌呤受体 6 多肽或使编码 P2Y 嘌呤受体 6 的核酸失活、降解、下调或插入或下调 P2Y 嘌呤受体 6 信号通路的化合物，以治疗与能量平衡以及碳水化合物代谢和稳态有关的疾病，优选葡萄糖代谢和稳态。本发明还涉及用于激活 P2Y 嘌呤受体 6 多肽或上调或修饰编码 P2Y 嘌呤受体 6 的核酸的高级转录活性、上调 P2Y 嘌呤受体 6 信号通路的化合物，以增加体重或治疗与能量平衡和碳水化合物代谢及平衡有关的疾病。本发明进一步涉及鉴定所述化合物是否适用于治疗与能量平衡和碳水化合物代谢及平衡有关的疾病的方法。本发明进一步涉及治疗和诊断与能量平衡和碳水化合物代谢及稳态相关疾病及相关并发症的方法。
• Methods of modulating immune activity
  申请人：Flagship Pioneering Innovations V, Inc.

  公开号：US11376272B2

  公开（公告）日：2022-07-05

  In one aspect, the invention provides methods of increasing immune response by administering postcellular signaling factors produced by cells exposed to a stress condition. In one aspect, the invention provides methods of increasing immune response by administering in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a purinergic receptor agonist. The increase in immune response may be used, for example, for treatment of infection or cancer. The invention also provides screening assays for identification of compounds that induce production of postcellular signaling factors which are also immunostimulatory agents. The invention further provides methods for identifying postcellular signaling factors with immunostimulatory activity. In another aspect, the invention provides methods of decreasing immune response by administering to a cell, tissue or subject a purinergic receptor antagonist alone or in combination with a Stimulator of Interferon Genes (STING) antagonist.

  一方面，本发明提供了通过施用暴露于应激条件下的细胞产生的细胞后信号因子来提高免疫应答的方法。在一个方面，本发明提供了通过联合施用(a)干扰素基因刺激剂（STING）激动剂和(b)嘌呤能受体激动剂来增加免疫反应的方法。免疫反应的增强可用于治疗感染或癌症等。本发明还提供了筛选测定法，用于鉴定能诱导产生细胞后信号因子的化合物，这些细胞后信号因子也是免疫刺激剂。本发明进一步提供了鉴定具有免疫刺激活性的细胞后信号因子的方法。在另一方面，本发明提供了通过向细胞、组织或受试者单独施用嘌呤能受体拮抗剂或与干扰素基因刺激剂（STING）拮抗剂联合施用来降低免疫反应的方法。
• FOOD INTAKE, BODY WEIGHT AND GLUCOSE METABOLISM REGULATION BY MODULATION OF P2Y6 RECEPTOR SIGNALING
  申请人：Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.

  公开号：US20180325933A1

  公开（公告）日：2018-11-15

  The present invention is related to compound capable of regulating the activity of P2Y purinoceptor 6 signaling pathway, especially to compounds for inhibition of P2Y purinoceptor 6 polypeptide or inactivation, degradation, downregulation or intercalation of a nucleic acid encoding P2Y purinoceptor 6 or downregulation of P2Y purinoceptor 6 signaling pathway for the treatment of diseases related to energy balance as well as carbohydrate metabolism and homeostasis, preferably glucose metabolism and homeostasis. The present is also related to compounds for activation of P2Y purinoceptor 6 polypeptide or upregulation or modification for advanced transcriptional activity of a nucleic acid encoding P2Y purinoceptor 6, upregulation of P2Y purinoceptor 6 signaling pathway for gaining weight or for the treatment of diseases related to energy balance and carbohydrate metabolism and homeostasis. The invention is further related to methods of identifying said compounds suitable for the treatment of diseases related to energy balance and carbohydrate metabolism and homeostasis. The invention is further related to methods of treatment and diagnosis of diseases related to energy balance and carbohydrate metabolism and homeostasis and associated complications.
• METHODS OF MODULATING IMMUNE ACTIVITY
  申请人：Flagship Pioneering Innovations V, Inc.

  公开号：US20210299155A1

  公开（公告）日：2021-09-30

  In one aspect, the invention provides methods of increasing immune response by administering posteellular signaling factors produced by cells exposed to a stress condition. In one aspect, the invention provides methods of increasing immune response by administering in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a purinergic receptor agonist. The increase in immune response may be used, for example, for treatment of infection or cancer. The invention also provides screening assays for identification of compounds that induce production of postcellular signaling factors which are also immunostimulatory agents. The invention further provides methods for identifying postcellular signaling factors with immunostimulatory activity. In another aspect, the invention provides methods of decreasing immune response by administering to a cell, tissue or subject a purinergic receptor antagonist alone or in combination with a Stimulator of Interferon Genes (STING) antagonist.