2-(3-Oxo-1-(4-phenylthiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)propyl)-malonic acid | 1221964-27-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(3-Oxo-1-(4-phenylthiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)propyl)-malonic acid
• 英文别名: 2-[3-Oxo-1-(4-phenylthiophen-2-yl)-3-[4-(trifluoromethyl)phenyl]propyl]propanedioic acid
• CAS: 1221964-27-7
• 化学式: C₂₃H₁₇F₃O₅S
• 分子量: 462.446
• InChiKey: ZIHRPLXMELCJIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-苯基噻吩-2-甲醛 在 magnesium oxide 、 sodium hydroxide 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 7.0h， 生成 2-(3-Oxo-1-(4-phenylthiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)propyl)-malonic acid
  参考文献：
  名称：

  2-(3-Oxo-1,3-diphenylpropyl)malonic Acids as Potent Allosteric Ligands of the PIF Pocket of Phosphoinositide-Dependent Kinase-1: Development and Prodrug Concept

  摘要：

  The protein kinase C-related kinase 2 (PRK2)interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, We describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3- diphenylprapyl)malonic acids as potent allosteric activators binding, to the PIF pocket: Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order Of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the pm pocket, The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1 Employing a prodrug strategy, we were able to corrroborate the novel mechanism of action in cells.

  DOI：

  10.1021/jm3010477

文献信息

• [EN] ALLOSTERIC PROTEIN KINASE MODULATORS<br/>[FR] MODULATEURS DE PROTÉINE KINASE ALLOSTÉRIQUE
  申请人：UNIV SAARLAND

  公开号：WO2010043711A1

  公开（公告）日：2010-04-22

  The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.

  该发明提供特定的小分子化合物，这些化合物能够变构调节AGC蛋白激酶的活性或调节Aurora家族蛋白激酶的蛋白-蛋白相互作用，提供这些化合物的制备方法，包含这些化合物的药物组合物，以及它们用于制备治疗和预防与AGC蛋白激酶或Aurora家族蛋白激酶异常活动相关疾病的药物的应用。
• ALLOSTERIC PROTEIN KINASE MODULATORS
  申请人：Engel Matthias

  公开号：US20120046307A1

  公开（公告）日：2012-02-23

  The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.

  本发明提供了特定的小分子化合物，它们通过变构调节AGC蛋白激酶的活性或调节Aurora家族蛋白激酶的蛋白质-蛋白质相互作用，其生产方法，包含该化合物的药物组合物，以及它们用于制备治疗和预防与AGC蛋白激酶或Aurora家族蛋白激酶异常活动相关疾病的药物的应用。
• US8912186B2
  申请人：——

  公开号：US8912186B2

  公开（公告）日：2014-12-16
• 2-(3-Oxo-1,3-diphenylpropyl)malonic Acids as Potent Allosteric Ligands of the PIF Pocket of Phosphoinositide-Dependent Kinase-1: Development and Prodrug Concept
  作者：Adriana Wilhelm、Laura A. Lopez-Garcia、Katrien Busschots、Wolfgang Fröhner、Frauke Maurer、Stefan Boettcher、Hua Zhang、Jörg O. Schulze、Ricardo M. Biondi、Matthias Engel

  DOI：10.1021/jm3010477

  日期：2012.11.26

  The protein kinase C-related kinase 2 (PRK2)interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, We describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3- diphenylprapyl)malonic acids as potent allosteric activators binding, to the PIF pocket: Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order Of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the pm pocket, The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1 Employing a prodrug strategy, we were able to corrroborate the novel mechanism of action in cells.