N-(6-(3-(benzyloxy)phenoxy)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,2-dimethyl-1H-imidazole-4-sulfonamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(6-(3-(benzyloxy)phenoxy)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,2-dimethyl-1H-imidazole-4-sulfonamide
• 英文别名: N-{6-[3-(benzyloxy)phenoxy]-1,3-dimethyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl}-1,2-dimethyl-1H-imidazole-4-sulfonamide；N-[1,3-dimethyl-2-oxo-6-(3-phenylmethoxyphenoxy)benzimidazol-5-yl]-1,2-dimethylimidazole-4-sulfonamide
• 化学式: C₂₇H₂₇N₅O₅S
• 分子量: 533.608
• InChiKey: ADCUUXTZXWDEEX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-氨基-1,3-二甲基-1,3-二氢-2H-苯并咪唑-2-酮 在 吡啶 、 potassium phosphate 、 8-羟基喹啉 、 溴 、 copper(l) chloride 作用下， 以 二氯甲烷 、 氯仿 、 二乙二醇二甲醚 、 溶剂黄146 为溶剂， 反应 72.5h， 生成 N-(6-(3-(benzyloxy)phenoxy)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,2-dimethyl-1H-imidazole-4-sulfonamide
  参考文献：
  名称：

  Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor

  摘要：

  The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethyl-benzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC K-d = 31 nM and ITC K-d = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.

  DOI：

  10.1021/acs.jmedchem.5b00405

文献信息

• BROMODOMAIN INHIBITORS FOR TREATING DISEASE
  申请人：Board of Regents, The University of Texas System

  公开号：US20160060260A1

  公开（公告）日：2016-03-03

  Disclosed herein are compounds and compositions useful in the treatment of bromodomain-containing protein-mediated diseases, such as cancer, having the structure of Formula I: Methods of inhibiting activity of a bromodomain-containing protein in a human or animal subject are also provided.

  本文披露了一种在治疗溴结构域含蛋白介导的疾病（如癌症）中有用的化合物和组合物，其具有Formula I的结构： 还提供了一种抑制人类或动物主体中溴结构域含蛋白活性的方法。
• [EN] BROMODOMAIN INHIBITORS FOR TREATING DISEASE<br/>[FR] INHIBITEURS DE BROMODOMAINE POUR LE TRAITEMENT DE MALADIES
  申请人：UNIV TEXAS

  公开号：WO2016033416A1

  公开（公告）日：2016-03-03

  Disclosed herein are compounds and compositions useful in the treatment of bromodomain-containing protein-mediated diseases, such as cancer, having the structure of Formula I: Methods of inhibiting activity of a bromodomain-containing protein in a human or animal subject are also provided.
• Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor
  作者：Wylie S. Palmer、Guillaume Poncet-Montange、Gang Liu、Alessia Petrocchi、Naphtali Reyna、Govindan Subramanian、Jay Theroff、Anne Yau、Maria Kost-Alimova、Jennifer P. Bardenhagen、Elisabetta Leo、Hannah E. Shepard、Trang N. Tieu、Xi Shi、Yanai Zhan、Shuping Zhao、Michelle C. Barton、Giulio Draetta、Carlo Toniatti、Philip Jones、Mary Geck Do、Jannik N. Andersen

  DOI：10.1021/acs.jmedchem.5b00405

  日期：2016.2.25

  The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethyl-benzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC K-d = 31 nM and ITC K-d = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.