3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-(4,4-difluoropiperidin-1-ylmethyl)phenol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-(4,4-difluoropiperidin-1-ylmethyl)phenol
• 英文别名: 3-[[4,4-Bis(fluoranyl)piperidin-1-yl]methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol；3-[(4,4-difluoropiperidin-1-yl)methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol
• 化学式: C₁₇H₂₀F₂N₂O₂
• 分子量: 322.355
• InChiKey: ASWANVCVFDVNLN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  49.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-溴-5-羟基苯甲醛 在 sodium carbonate 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 19.5h， 生成 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-(4,4-difluoropiperidin-1-ylmethyl)phenol
  参考文献：
  名称：

  BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

  摘要：

  Ligands for the bromodomain and extra terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the ReIA subunit of NF-kappa B, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2) = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBDO4 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t(1/2) = 388 min). (C) 2018 The Authors. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2018.05.003

文献信息

• BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
  作者：Laura E. Jennings、Matthias Schiedel、David S. Hewings、Sarah Picaud、Corentine M.C. Laurin、Paul A. Bruno、Joseph P. Bluck、Amy R. Scorah、Larissa See、Jessica K. Reynolds、Mustafa Moroglu、Ishna N. Mistry、Amy Hicks、Pavel Guzanov、James Clayton、Charles N.G. Evans、Giulia Stazi、Philip C. Biggin、Anna K. Mapp、Ester M. Hammond、Philip G. Humphreys、Panagis Filippakopoulos、Stuart J. Conway

  DOI：10.1016/j.bmc.2018.05.003

  日期：2018.7

  Ligands for the bromodomain and extra terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the ReIA subunit of NF-kappa B, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2) = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBDO4 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t(1/2) = 388 min). (C) 2018 The Authors. Published by Elsevier Ltd.