2-chloro-N-(4-chloro-3-(piperidin-1-ylsulfonyl)phenyl)acetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-chloro-N-(4-chloro-3-(piperidin-1-ylsulfonyl)phenyl)acetamide
• 英文别名: 2-chloro-N-[4-chloro-3-(piperidin-1-ylsulfonyl)phenyl]acetamide；2-chloro-N-(4-chloro-3-piperidin-1-ylsulfonylphenyl)acetamide
• 化学式: C₁₃H₁₆Cl₂N₂O₃S
• mdl: MFCD08444132
• 分子量: 351.254
• InChiKey: NMKMSYQBPDKDDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.461
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  海因 、 2-chloro-N-(4-chloro-3-(piperidin-1-ylsulfonyl)phenyl)acetamide 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 0.5h， 以10%的产率得到N-(4-chloro-3-(piperidin-1-ylsulfonyl)phenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetamide
  参考文献：
  名称：

  具有非典型结合模式的有效ATAD2和CECR2溴结构域抑制剂的优化。

  摘要：

  大多数溴结构域抑制剂通过与结合口袋中保守的天冬酰胺和酪氨酸残基的关键相互作用来模拟天然乙酰化赖氨酸（KAc）组蛋白底物的相互作用。本文中，我们报告了一系列苯基磺酰胺的优化，这些苯基磺酰胺通过置换四个水分子的通常保守的网络，表现出与非溴结构域和额外末端结构域（非BET）溴结构域结合的新型模式。从最初的命中分子开始，我们报告了其对包含2个（ATAD2）和猫眼综合征染色体区域，候选2个（CECR2）域的ATPase家族AAA域的不同优化。这项工作结束于鉴定（R）-55（GSK232），这是一种具有优异理化特性的高选择性，细胞渗透性CECR2抑制剂。

  DOI：

  10.1021/acs.jmedchem.0c00021

文献信息

• A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification
  作者：Paul Bamborough、Chun-wa Chung、Emmanuel H. Demont、Angela M. Bridges、Peter D. Craggs、David P. Dixon、Peter Francis、Rebecca C. Furze、Paola Grandi、Emma J. Jones、Bhumika Karamshi、Kelly Locke、Simon C. C. Lucas、Anne-Marie Michon、Darren J. Mitchell、Peter Pogány、Rab K. Prinjha、Christina Rau、Ana Maria Roa、Andrew D. Roberts、Robert J. Sheppard、Robert J. Watson

  DOI：10.1021/acs.jmedchem.9b00673

  日期：2019.8.22

  The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less tractable targets.