4-(3-(4-((3-fluorophenyl)(hydroxy)(pyridin-2-yl)methyl)piperidin-1-yl)-2-hydroxypropoxy)benzonitrile

• 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-((3-fluorophenyl)(hydroxy)(pyridin-2-yl)methyl)piperidin-1-yl)-2-hydroxypropoxy)benzonitrile
• 英文别名: 4-[3-[4-[(3-Fluorophenyl)-hydroxy-pyridin-2-ylmethyl]piperidin-1-yl]-2-hydroxypropoxy]benzonitrile；4-[3-[4-[(3-fluorophenyl)-hydroxy-pyridin-2-ylmethyl]piperidin-1-yl]-2-hydroxypropoxy]benzonitrile
• 化学式: C₂₇H₂₈FN₃O₃
• 分子量: 461.536
• InChiKey: CRNUPAOLDIWHGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  7

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 、 乙腈 为溶剂， 反应 6.0h， 生成 4-(3-(4-((3-fluorophenyl)(hydroxy)(pyridin-2-yl)methyl)piperidin-1-yl)-2-hydroxypropoxy)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

• 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。
• 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.