N-[[[[3-苄基氨基)苯基]氨基]硫代甲基]-3,4,5-三甲氧基苯甲酰胺 | 330829-30-6

• 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: N-[[[[3-苄基氨基)苯基]氨基]硫代甲基]-3,4,5-三甲氧基苯甲酰胺
• 英文名称: MRT-10
• 英文别名: N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide；N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide；N-[[[3-[(Benzoyl)amino]phenyl]amino](thioxo)methyl]-3,4,5-trimethoxybenzamide；N-[(3-benzamidophenyl)carbamothioyl]-3,4,5-trimethoxybenzamide
• CAS: 330829-30-6
• 化学式: C₂₄H₂₃N₃O₅S
• 分子量: 465.53
• InChiKey: KVQVEZQDNHMQJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[[[[3-苄基氨基)苯基]氨基]硫代甲基]-3,4,5-三甲氧基苯甲酰胺 在 copper(l) chloride 、 sodium hydroxide 作用下， 以 乙腈 为溶剂， 120.0 ℃ 、344.75 kPa 条件下， 反应 0.1h， 以55%的产率得到MRT-14
  参考文献：
  名称：

  Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity

  摘要：

  The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

  DOI：

  10.1021/jm2013369
• 作为产物：
  描述：

  3,4,5-三甲氧基苯甲酸 在 草酰氯 作用下， 以 丙酮 为溶剂， 反应 1.33h， 生成 N-[[[[3-苄基氨基)苯基]氨基]硫代甲基]-3,4,5-三甲氧基苯甲酰胺
  参考文献：
  名称：

  Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity

  摘要：

  The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

  DOI：

  10.1021/jm2013369

文献信息

• Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists
  作者：Fabrizio Manetti、Helene Faure、Hermine Roudaut、Tatiana Gorojankina、Elisabeth Traiffort、Angele Schoenfelder、Andre Mann、Antonio Solinas、Maurizio Taddei、Martial Ruat

  DOI：10.1124/mol.110.065102

  日期：2010.10

  The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N -(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N -(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N -((3 S ,5 S )-1-(benzo\[ d \]\[1,3\]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)- N -(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.

  七次跨膜受体Smoothened（Smo）是Hedgehog（Hh）形态发生素信号传导的主要组成部分。Smo抑制剂为治疗与异常Hh信号传导相关的几种癌症提供了一种有希望的选择。在此，基于实验数据，我们生成了并验证了一个由三个氢键受体基团和三个疏水区域组成的针对Smo抑制剂的药效模型。我们利用这个模型对一个商业可获得的化合物库进行了虚拟筛选。通过视觉和结构标准，选出了20个得分最高的配体，并鉴定和表征了一种酰基硫脲，N-(3-苯甲酰胺苯基氨基甲酰硫基)-3,4,5-三甲氧基苯甲酰胺（MRT-10），作为一种Smo拮抗剂。相应的酰基脲，N-(3-苯甲酰胺苯基氨基甲酰基)-3,4,5-三甲氧基苯甲酰胺（MRT-14）被合成，并展示在各种Hh检测中，其抑制效力与参考Smo拮抗剂环巴胺和N-((3S,5S)-1-(苯并[d][1,3]二氧杂环-5-基甲基)-5-(哌嗪-1-羰基)吡咯烷-3-基)-N-(3-甲氧基苄基)-3,3-二甲基丁酰胺（Cur61414）相当或更高。对该库的集中虚拟筛选进一步鉴定了五个额外的相关拮抗剂。MRT-10和MRT-14构成了新型Smo拮抗剂家族的首次成员。所描述的虚拟筛选方法旨在识别Smo和其他G蛋白偶联受体的新型调制因子。
• N-Acylthiourea and N-Acylurea Inhibitors of the Hedgehog Protein Signalling Pathway
  申请人：Ruat Martial

  公开号：US20110275663A1

  公开（公告）日：2011-11-10

  The present invention relates to the use of acylthiourea or acylurea derivatives for the treatment of pathologies involving a tissue dysfunction associated with a deregulation of the Hedgehog protein signalling pathway, and also to novel acylthiourea or acylurea derivatives as such, to their use as a medicinal product, and to pharmaceutical compositions containing them.

  本发明涉及使用酰基硫脲或酰基脲衍生物治疗涉及组织功能障碍的病理情况，该功能障碍与Hedgehog蛋白信号通路的失调有关，并且涉及作为药物产品的新型酰基硫脲或酰基脲衍生物，它们的用途以及含有它们的药物组成物。
• N-ACYLTHIOUREES ET N-ACYLUREES INHIBITEURS DE LA VOIE DE SIGNALISATION DES PROTEINES HEDGEHOG
  申请人：Centre National de la Recherche Scientifique

  公开号：EP2291352B1

  公开（公告）日：2017-09-13
• US9073835B2
  申请人：——

  公开号：US9073835B2

  公开（公告）日：2015-07-07
• [EN] N-ACYLTHIOUREA AND N-ACYLUREA INHIBITORS OF THE HEDGEHOG PROTEIN SIGNALLING PATHWAY<br/>[FR] N-ACYLTHIOUREES ET N-ACYLUREES INHIBITEURS DE LA VOIE DE SIGNALISATION DES PROTEINES HEDGEHOG
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2009130422A2

  公开（公告）日：2009-10-29

  La présente invention est relative à l'utilisation de dérivés d'acyl- thiourées ou d'acyl-urées pour le traitement de pathologies impliquant un dysfonctionnement tissulaire lié à une dérégulation de la voie de signalisation des protéines Hedgehog, ainsi qu'à de nouveaux dérivés d'acyl-thiourées ou d'acyl-urées en tant que tels, à leur utilisation comme médicament, et aux compositions pharmaceutiques les contenant.