PI-1833 | 708994-70-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: PI-1833
• 英文别名: N-isopropyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide；2-(4-methylphenoxy)-N-[[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]-N-propan-2-ylacetamide
• CAS: 708994-70-1
• 化学式: C₂₂H₂₅N₃O₃
• 分子量: 379.459
• InChiKey: MZPIETOIDSVGGL-UHFFFAOYSA-N

物化性质

• 沸点：
  556.4±60.0 °C(Predicted)
• 密度：
  1.155±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  68.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (4-甲基苯氧基)乙酸 在 氯化亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 苯 为溶剂， 反应 3.25h， 生成 PI-1833
  参考文献：
  名称：

  恶二唑-异丙基酰胺作为有效的非共价蛋白酶体抑制剂

  摘要：

  对 50 000 ChemBridge 化合物库的筛选导致鉴定出恶二唑-异丙基酰胺1 (PI-1833)，其抑制胰凝乳蛋白酶样 (CT-L) 活性（IC 50 = 0.60 μM），对其他两种主要蛋白酶体几乎没有影响蛋白水解活性，胰蛋白酶样 (TL) 和谷氨酰肽水解样 (PGPH-L)。LC-MS/MS 和透析表明1是一种非共价且快速可逆的 CT-L 抑制剂。集中文库合成为11ad (PI-1840) 提供了 CT-L 活性 (IC 50= 27 纳米）。详细的 SAR 研究表明酰胺部分和两个苯环对修饰敏感。疏水性残基，如在对位丙基或丁基（未邻位或间位）的A环和一个的米-吡啶基团作为B环，显著提高活性。化合物11ad (IC 50 = 0.37 μM)在抑制完整 MDA-MB-468 人乳腺癌细胞中的 CT-L 活性和抑制其存活方面比1 (IC 50 = 3.5 μM)更有效。11ad的活

  DOI：

  10.1021/jm400221d

文献信息

• PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc

  公开号：US20140073650A1

  公开（公告）日：2014-03-13

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  聚焦于氧代二唑-异丙酰胺核心蛋白酶体抑制剂的合成和药物化学，提供了一种强烈抑制CT-L活性的先导化合物。结构活性关系研究表明，酰胺基团和两个苯环对合成修饰非常敏感。只有在A环上的对位取代对维持强效的CT-L抑制活性至关重要。A环对位的疏水基团和B环的间吡啶基团显著提高了抑制作用。间吡啶基团提高了细胞渗透性。A环对位的脂肪链长度是关键，丙基产生了最有效的抑制剂，而较短（即乙基，甲基或氢）或较长（即丁基，异丙基和己基）的链逐渐表现出较少的效力。在醚基团旁引入一个立体异构中心（即将一个氢原子取代为甲基）表明在蛋白酶体CT-L活性抑制中具有手性歧视（S-对映体比R-对映体更有效，效力提高了35-40倍）。
• Proteasome chymotrypsin-like inhibition using PI-1833 analogs
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc.

  公开号：US10662180B2

  公开（公告）日：2020-05-26

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  通过对一种噁二唑-异丙基酰胺核心蛋白酶体抑制剂进行重点文库合成和药物化学研究，获得了能强烈抑制 CT-L 活性的先导化合物。结构活性关系研究表明，酰胺分子和两个苯基环对合成修饰很敏感。只有 A 环中的对位取代对保持 CT-L 的强效抑制活性非常重要。A 环的对位疏水残基和 B 环的元吡啶基能显著改善抑制作用。偏吡啶基提高了细胞渗透性。A 环对位脂肪族链的长度至关重要，丙基产生的抑制作用最强，而较短的链（即乙基、甲基或氢基）或较长的链（即丁基、丙基和己基）的抑制作用则逐渐减弱。在醚分子旁边引入一个立体中心（即用甲基取代其中一个氢）可在蛋白酶体 CT-L 活性抑制方面显示出手性差异（S-对映体的效力比 R-对映体高 35-40 倍）。
• Methods and compositions relating to proteasome inhibitor resistance
  申请人：Whitehead Institute for Biomedical Research

  公开号：US11092602B2

  公开（公告）日：2021-08-17

  In some aspects, the disclosure provides methods of modulating the level of proteasome inhibitor resistance of a cell, the methods comprising manipulating the level of expression or activity of a subunit of the 19S proteasome in the cell. In some aspects, cells in which the level of a 19S subunit is modulated, e.g., reduced, are provided. In some aspects, methods of identifying agents that reduce proteasome inhibitor resistance are provided. In some aspects, methods of classifying cancers according to predicted proteasome inhibitor resistance are provided. In some aspects, methods of killing or inhibiting proliferation of cancer cells, e.g., proteasome inhibitor resistant cancer cells, are provided. In some aspects, methods of treating cancer, e.g., proteasome inhibitor resistant cancer, are provided.

  在某些方面，本公开提供了调节细胞蛋白酶体抑制剂抗性水平的方法，这些方法包括操纵细胞中 19S 蛋白酶体亚基的表达水平或活性。在某些方面，提供了 19S 亚基水平被调节（如降低）的细胞。在某些方面，提供了鉴定降低蛋白酶体抑制剂耐药性的制剂的方法。在某些方面，提供了根据预测的蛋白酶体抑制剂耐药性对癌症进行分类的方法。在某些方面，提供了杀死或抑制癌细胞（如蛋白酶体抑制剂抗性癌细胞）增殖的方法。在某些方面，提供了治疗癌症（例如蛋白酶体抑制剂抗性癌症）的方法。
• [EN] PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS<br/>[FR] INHIBITION DE CHYMOTRYPSINE-LIKE DU PROTÉASOME À L'AIDE D'ANALOGUES DE PI-1833
  申请人：H LEE MOFFITT CANCER CT & RES

  公开号：WO2012129564A3

  公开（公告）日：2012-12-27
• US9878999B2
  申请人：——

  公开号：US9878999B2

  公开（公告）日：2018-01-30