3-(4-isopropylphenoxy)-9-(3-phenylpropylamino)-8H-acenaphtho[1,2-b]pyrrol-8-one | 1416085-59-0

• 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: 3-(4-isopropylphenoxy)-9-(3-phenylpropylamino)-8H-acenaphtho[1,2-b]pyrrol-8-one
• 英文别名: 3-(4-isopropylphenoxy)-9-(3-phenylpropylamino)-acenaphtho[1,2-b]pyrrol-8-one；9-(3-phenylpropylimino)-3-(4-propan-2-ylphenoxy)-7H-acenaphthyleno[1,2-b]pyrrol-8-one
• CAS: 1416085-59-0
• 化学式: C₃₂H₂₈N₂O₂
• 分子量: 472.587
• InChiKey: UQGNXYDWNJQPQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  50.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-(4-isopropylphenoxy)acenaphthenequinone 在 silica gel 、 potassium carbonate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 3.0h， 生成 3-(4-isopropylphenoxy)-9-(3-phenylpropylamino)-8H-acenaphtho[1,2-b]pyrrol-8-one
  参考文献：
  名称：

  3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1

  摘要：

  Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.008

文献信息

• ACENAPHTHO HETEROCYCLIC COMPOUND AND APPLICATION THEREOF
  申请人：Zhang Zhichao

  公开号：US20130123492A1

  公开（公告）日：2013-05-16

  The present invention relates to acenaphtho heterocyclic compounds and their uses in manufacturing the BH3 mimetics as Bcl-2-like protein inhibitors. Structures are shown in the following: Statistical analysis of their bio-activities showed these compounds exhibit better BH3 mimicking property than the reported compounds. These compounds can simulate BH3-only protein, competitively bind and antagonizing Bcl-2 and Mcl-1 proteins in vitro and in cells, and then induce apoptosis. Therefore, they all can be used in the manufactures of anticancer compounds.

  本发明涉及蒽醌杂环化合物及其在制造类似Bcl-2蛋白抑制剂的BH3模拟物中的用途。结构如下所示：对它们的生物活性进行的统计分析表明，这些化合物表现出比已报告的化合物更好的BH3模拟性能。这些化合物可以模拟BH3-只蛋白，在体外和细胞中与Bcl-2和Mcl-1蛋白竞争性结合和拮抗，然后诱导细胞凋亡。因此，它们都可以用于抗癌化合物的制造。
• [EN] THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR, AND/OR A BCL-2 INHIBITOR<br/>[FR] COMBINAISONS THÉRAPEUTIQUES D'UN INHIBITEUR DE BTK, D'UN INHIBITEUR DE PI3K, D'UN INHIBITEUR DE JAK-2, ET/OU D'UN INHIBITEUR DE BCL-2
  申请人：ACERTA PHARMA BV

  公开号：WO2016024230A1

  公开（公告）日：2016-02-18

  Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.

  本发明描述了磷脂酰肌醇3-激酶（PI3K）抑制剂的治疗组合，包括选择性作用于γ-和δ-异构体以及同时选择性作用于γ-和δ-异构体（PI3K-γ,δ, PI3K-γ和PI3K-δ）的PI3K抑制剂，一种Janus激酶-2（JAK-2）抑制剂，一种Bruton酪氨酸激酶（BTK）抑制剂，和/或一种B细胞淋巴瘤-2（BCL-2）抑制剂。在一些实施例中，本发明提供了PI3K-δ抑制剂和BTK抑制剂、JAK-2和BTK抑制剂、以及BCL-2和BTK抑制剂的治疗组合。
• Therapeutic combinations of a BTK inhibitor, a PI3K inhibitor, a JAK-2 inhibitor, and/or a BCL-2 inhibitor
  申请人：Acerta Pharma B.V.

  公开号：US11166951B2

  公开（公告）日：2021-11-09

  Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.

  磷脂酰肌醇 3-激酶（PI3K）抑制剂的治疗组合，包括对γ-和δ-异构体有选择性的 PI3K 抑制剂以及对γ-和δ-异构体均有选择性的 PI3K 抑制剂（PI3K-γ、PI3K-γ 和 PI3K-δ）、δ、PI3K-γ 和 PI3K-δ）的选择性抑制剂、Janus 激酶-2 (JAK-2) 抑制剂、布鲁顿酪氨酸激酶 (BTK) 抑制剂和/或 B 细胞淋巴瘤-2 (BCL-2) 抑制剂。在一些实施方案中，本发明提供了PI3K-δ抑制剂和BTK抑制剂、JAK-2和BTK抑制剂以及BCL-2和BTK抑制剂的治疗组合。
• THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR, AND/OR A BCL-2 INHIBITOR
  申请人：Acerta Pharma B.V.

  公开号：EP3179991A1

  公开（公告）日：2017-06-21
• Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
  申请人：Acerta Pharma B.V.

  公开号：US20170231986A1

  公开（公告）日：2017-08-17

  Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.