(R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)oxy)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)oxy)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
• 英文别名: DB-1-205；BRD4 Inhibitor-30；4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]oxy]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
• 化学式: C₂₈H₃₈N₆O₄
• 分子量: 522.648
• InChiKey: MLSIWMLVUIWYLH-OAQYLSRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (7R)-2-氯-8-环戊烷基-7-乙基-7,8-二氢-6(5H)-蝶啶酮 在 盐酸 、 sodium hydride 作用下， 以 1,4-二氧六环 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)oxy)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
  参考文献：
  名称：

  BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

  摘要：

  A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K-i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.

  DOI：

  10.1021/acsmedchemlett.5b00084

文献信息

• [EN] DIHYDROPTERIDINONE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE DIHYDROPTÉRIDINONE ET LEURS UTILISATIONS
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2015117055A1

  公开（公告）日：2015-08-06

  The present invention provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain- containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

  本发明提供了化合物的结构式（I），以及其药用组合物。结构式（I）的化合物是溴结构域和/或含有溴结构域蛋白（例如，溴和额外末端（BET）蛋白）的结合物。还提供了使用这些化合物和药用组合物的方法、用途和工具包，用于抑制溴结构域和/或含有溴结构域蛋白的活性（例如，增加活性），并用于治疗和/或预防与溴结构域或含有溴结构域蛋白相关的疾病（例如，增殖性疾病、心血管疾病、病毒感染、纤维化性疾病、代谢性疾病、内分泌性疾病和辐射中毒）。这些化合物、药用组合物和工具包也适用于男性避孕。
• Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET‐BRET
  作者：Luke W. Koblan、Dennis L. Buckley、Christopher J. Ott、Mark E. Fitzgerald、Stuart W. J. Ember、Jin‐Yi Zhu、Shuai Liu、Justin M. Roberts、David Remillard、Sarah Vittori、Wei Zhang、Ernst Schonbrunn、James E. Bradner

  DOI：10.1002/cmdc.201600502

  日期：2016.12.6

  classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain‐ and kinase‐biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain‐selective specificity

  评估小分子配体与细胞中蛋白质靶标的结合为化学探针优化和药物开发提供了有用的信息。虽然存在可以以低通量方式执行的几种技术，但对大型化合物库的系统评估仍然是一个挑战。在评估怀疑针对多个细胞因子的化合物类别时，细胞内参与测量特别有用。在这项研究中，我们使用生物发光共振能量转移测定来评估基于已知双 BRD4 溴结构域/PLK1 激酶抑制剂 BI2536 的包含溴结构域和激酶偏向多药团的化合物系列的溴结构域参与。通过该测定，我们发现了几种具有溴结构域选择性特异性特征和细胞活性的新型药物。因此，
• Combination therapy of transcription inhibitors and kinase inhibitors
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10702527B2

  公开（公告）日：2020-07-07

  The present disclosure provides combination therapy of a transcription inhibitor and a kinase inhibitor. The combination of the transcription inhibitor and the kinase inhibitor may be useful in treating and/or preventing in a subject a proliferative disease, such as proliferative a disease that is resistant to the transcription inhibitor alone or the kinase inhibitor alone. In certain embodiments, the proliferative disease is a cancer. The combination of the transcription inhibitor and the kinase inhibitor is expected to be synergistic.

  本公开提供了转录抑制剂和激酶抑制剂的组合疗法。转录抑制剂和激酶抑制剂的组合可用于治疗和/或预防受试者的增殖性疾病，如对单独转录抑制剂或单独激酶抑制剂耐药的增殖性疾病。在某些实施方案中，增殖性疾病是癌症。转录抑制剂和激酶抑制剂的组合可望产生协同作用。
• DIHYDROPTERIDINONE DERIVATIVES AND USES THEREOF
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20160347750A1

  公开（公告）日：2016-12-01

  The present invention provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.
• COMBINATION THERAPY OF TRANSCRIPTION INHIBITORS AND KINASE INHIBITORS
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20180169097A1

  公开（公告）日：2018-06-21

  The present disclosure provides combination therapy of a transcription inhibitor and a kinase inhibitor. The combination of the transcription inhibitor and the kinase inhibitor may be useful in treating and/or preventing in a subject a proliferative disease, such as proliferative a disease that is resistant to the transcription inhibitor alone or the kinase inhibitor alone. In certain embodiments, the proliferative disease is a cancer. The combination of the transcription inhibitor and the kinase inhibitor is expected to be synergistic.