4-(3-(4-(cyclopentyl(3-fluorophenyl)(hydroxy)methyl)piperidin-1-yl)propoxy)benzonitrile | 1560968-15-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-(3-(4-(cyclopentyl(3-fluorophenyl)(hydroxy)methyl)piperidin-1-yl)propoxy)benzonitrile
• 英文别名: 4-[3-[4-[Cyclopentyl-(3-fluorophenyl)-hydroxymethyl]piperidin-1-yl]propoxy]benzonitrile；4-[3-[4-[cyclopentyl-(3-fluorophenyl)-hydroxymethyl]piperidin-1-yl]propoxy]benzonitrile
• CAS: 1560968-15-1
• 化学式: C₂₇H₃₃FN₂O₂
• 分子量: 436.57
• InChiKey: FTSMDZBUBLYVKI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  56.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-Boc-4-[甲氧基(甲基)氨基甲酰]哌嗪 在 盐酸 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 4-(3-(4-(cyclopentyl(3-fluorophenyl)(hydroxy)methyl)piperidin-1-yl)propoxy)benzonitrile
  参考文献：
  名称：

  Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

  摘要：

  A series of substituted hydroxymethyl piperidine small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) are described. Initial members of the series showed good inhibitory disruption of the menin-MLL1 interaction but demonstrated poor physicochemical and DMPK properties. Utilizing a structure-guided and iterative optimization approach key substituents were optimized leading to inhibitors with cell-based activity, improved in vitro DMPK parameters, and improved half-lives in rodent PK studies leading to MLPCN probe ML399. Ancillary off-target activity remains a parameter for further optimization. (C) 2015 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2015.04.026

文献信息

• High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction
  作者：Shihan He、Timothy J. Senter、Jonathan Pollock、Changho Han、Sunil Kumar Upadhyay、Trupta Purohit、Rocco D. Gogliotti、Craig W. Lindsley、Tomasz Cierpicki、Shaun R. Stauffer、Jolanta Grembecka

  DOI：10.1021/jm401868d

  日期：2014.2.27

  The protein–protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin–MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS

  Menin 和混合谱系白血病 (MLL) 之间的蛋白质-蛋白质相互作用 (PPI) 在急性白血病中起着关键作用，抑制这种相互作用代表了 MLL 白血病新的潜在治疗策略。我们报告了一类新的menin-MLL相互作用的小分子抑制剂的开发，即羟基和氨甲基哌啶化合物，它们源自~288000个小分子的HTS。我们确定了menin-抑制剂共晶结构，发现这些化合物与MLL与menin的所有关键相互作用非常相似。广泛的晶体学研究与基于结构的设计相结合，用于优化这些化合物，产生MIV - 6 R，它抑制了 Menin-MLL 与 IC 50 的相互作用= 56 纳米。MIV - 6治疗在 MLL 白血病细胞中表现出强大的选择性作用，验证了特定的作用机制。我们的研究提供了新颖且有吸引力的支架作为 MLL 白血病的一种新的潜在治疗方法，并证明了 PPI 可以被小分子抑制的例子。
• MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF
  申请人：The Regents of The University of Michigan

  公开号：US20140371239A1

  公开（公告）日：2014-12-18

  The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperidine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.

  本发明通常涉及抑制menin和MLL或MLL融合蛋白结合的化合物以及其使用方法。在特定实施方案中，本发明提供包含哌啶类化合物的组合物，以及使用这些组合物来抑制menin与MLL致癌蛋白（例如MLL1、MLL2、MLL融合致癌蛋白）的相互作用的方法，例如用于治疗白血病、实体癌症、糖尿病以及其他依赖于MLL1、MLL2、MLL融合蛋白、MLL-PTD和/或menin活性的疾病。
• [EN] MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF<br/>[FR] INHIBITEURS DE MÉNINE-MLL ET MÉTHODES D'UTILISATION ASSOCIÉES
  申请人：UNIV MICHIGAN

  公开号：WO2014200479A1

  公开（公告）日：2014-12-18

  The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.

  本发明一般涉及抑制menin和MLL或MLL融合蛋白结合的化合物及其使用方法。特别是，在特定实施例中，本发明提供含有哌啶类化合物的组合物以及使用这些化合物的方法，以抑制menin与MLL致癌蛋白（例如MLL1、MLL2、MLL融合致癌蛋白）的相互作用，例如，用于治疗白血病、实体癌症、糖尿病以及依赖于MLL1、MLL2、MLL融合蛋白、MLL-PTD和/或menin活性的其他疾病。
• US9212180B2
  申请人：——

  公开号：US9212180B2

  公开（公告）日：2015-12-15
• Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility
  作者：Timothy Senter、Rocco D. Gogliotti、Changho Han、Charles W. Locuson、Ryan Morrison、J. Scott Daniels、Tomasz Cierpicki、Jolanta Grembecka、Craig W. Lindsley、Shaun R. Stauffer

  DOI：10.1016/j.bmcl.2015.04.026

  日期：2015.7

  A series of substituted hydroxymethyl piperidine small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) are described. Initial members of the series showed good inhibitory disruption of the menin-MLL1 interaction but demonstrated poor physicochemical and DMPK properties. Utilizing a structure-guided and iterative optimization approach key substituents were optimized leading to inhibitors with cell-based activity, improved in vitro DMPK parameters, and improved half-lives in rodent PK studies leading to MLPCN probe ML399. Ancillary off-target activity remains a parameter for further optimization. (C) 2015 Published by Elsevier Ltd.