4-(4-氯苯基)-4-[4-(1H-吡唑-4-基)苯基]哌啶 | 857531-00-1

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-(4-氯苯基)-4-[4-(1H-吡唑-4-基)苯基]哌啶
• 中文别名: AT-7867抑制剂；达格列净；AKT1/AKT2/AKT3和P70S6K/PKA抑制剂(AT7867)；化合物AT7867
• 英文名称: AT7867
• 英文别名: 4-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorophenyl)piperidine；4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine；OICR0008727；4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine
• CAS: 857531-00-1
• 化学式: C₂₀H₂₀ClN₃
• 分子量: 337.852
• InChiKey: LZMOSYUFVYJEPY-UHFFFAOYSA-N

物化性质

• 密度：
  1.214
• 溶解度：
  DMSO 中≥16.9 mg/mL； ≥4.38 mg/mL，乙醇溶液，超声波；水中≥45 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  40.7
• 氢给体数：
  2
• 氢受体数：
  2

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

AT7867 是一种有效的ATP竞争性Akt1/2/3和p70S6K/PKA抑制剂。其在无细胞试验中的IC50值分别为：Akt1（32 nM）、Akt2（17 nM）、Akt3（47 nM）和p70S6K（85 nM）、PKA（20 nM）。对AGC激酶家族以外几乎没有抑制活性。

体外研究

AT7867 还能抑制结构相关的AGC激酶 p70S6K 和 PKA，IC50分别为20 nM和85 nM。当其作用于AKT2时，Ki值为18 nM。在携带 PTEN 或 PIK3CA 突变的细胞系中，AT7867 表现出抗增殖活性，并高效作用于 MES-SA、MDA-MB-468、MCF-7、HCT116 和 HT29 细胞，IC50值分别为0.94 μM、2.26 μM、1.86 μM、1.76 μM和3.04 μM。同时，AT7867 也抑制了U87MG、PC-3 和DU145细胞生长，IC50值分别为8.22 μM、10.37 μM和11.86 μM。此外，通过抑制人类肿瘤细胞中GSK3β的磷酸化而抑制AKT活性，IC50为2-4 μM。在作用于U87MG细胞时，AT7867 也能诱导AKT直接底物的磷酸化，包括促凋亡转录因子FKHR (FoxO1a)、FKHRL1(FoxO3a)和下游靶点S6RP。

体内研究

AT7867 通过口服处理给药小鼠，生物有效性达到44%。按20 mg/kg剂量腹腔注射或90 mg/kg剂量口服给药MES-SA移植瘤时，能提高cleaved PARP水平，并显著抑制 MES-SA 移植瘤或 U87MG 移植瘤的生长，T/C值分别为0.37和0.51。

靶点

Target	Value
Akt2 (Cell-free assay)	17 nM
PKA (Cell-free assay)	20 nM
Akt1 (Cell-free assay)	32 nM
Akt3 (Cell-free assay)	47 nM
p70 S6K (Cell-free assay)	85 nM

反应信息

• 作为产物：
  描述：

  氯苯 在 二(三叔丁基膦)钯 potassium phosphate 、 三氯化铝 作用下， 以 various solvent(s) 为溶剂， 反应 32.0h， 生成 4-(4-氯苯基)-4-[4-(1H-吡唑-4-基)苯基]哌啶
  参考文献：
  名称：

  Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery

  摘要：

  Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein-ligand structure determinations using a PKA-PKB "chimera" and a final protein-ligand structure of a lead compound in PKBbeta itself.

  DOI：

  10.1021/jm070091b

文献信息

• TRIAZOLOPYRIMIDINE COMPOUNDS AND USES THEREOF
  申请人：CHAN Ho Man

  公开号：US20160176882A1

  公开（公告）日：2016-06-23

  A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined herein.

  提供了一种由化合物（I）或其药学上可接受的盐组成的药物，已被证明对治疗PRC2介导的疾病或紊乱有用：其中R1、R2、R3、R4、R5和n的定义如本文所述。
• [EN] IMIDAZOPYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS D'IMIDAZOPYRIMIDINE UTILES POUR LE TRAITEMENT DU CANCER
  申请人：NOVARTIS AG

  公开号：WO2017221100A1

  公开（公告）日：2017-12-28

  A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein A, R3, R4, R6, and R7 are as defined herein.

  提供了一种具有以下结构式（IA）的化合物，或其药用盐，已被证明对治疗PRC2介导的疾病或紊乱有用：其中A，R3，R4，R6和R7如本文所定义。
• [EN] PYRAZOLE DERIVATIVES AS PROTEIN KINASE MODULATORS<br/>[FR] DERIVES DE PYRAZOLE SERVANT DE MODULATEURS DE PROTEINE KINASE
  申请人：ASTEX TECHNOLOGY LTD

  公开号：WO2005061463A1

  公开（公告）日：2005-07-07

  The invention provides compounds of the formula: (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between Rl and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the inker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the NR2R3 group and provided that the oxo group when present is located at a carbon atom a with respect to the NR2R3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; Rl is an aryl or heteroaryl group; and R2, R3, R4 and R5 are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

  该发明提供了具有蛋白激酶B抑制活性的化合物，其化学式为：（I），其中A是一个饱和的含有1至7个碳原子的烷基链连接基团，该连接基团在R1和NR2R3之间延伸的最大链长为5个原子，在E和NR2R3之间延伸的最大链长为4个原子，其中连接基团中的一个碳原子可以选择性地被氧原子或氮原子取代；连接基团A的碳原子可以选择性地携带来自酮基、氟和羟基的一个或多个取代基，前提是当存在羟基时，该羟基不位于相对于NR2R3基团的碳原子a处，且当存在酮基时，该酮基位于相对于NR2R3基团的碳原子a处；E是一个单环或双环的碳环或杂环基团；R1是芳基或杂芳基团；R2、R3、R4和R5如权利要求中所定义。还提供了含有这些化合物的药物组合物，制备这些化合物的方法以及它们作为抗癌剂的用途。
• PHARMACEUTICAL COMBINATIONS COMPRISING PYRAZOLE DERIVATIVES AS PROTEIN KINASE MODULATORS
  申请人：Thompson Neil Thomas

  公开号：US20100166699A1

  公开（公告）日：2010-07-01

  The invention provides a combination comprising an ancillary compound (e.g. one, two or more ancillary compounds) and a compound of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R 1 and NR 2 R 3 and a maximum chain length of 4 atoms extending between E and NR 2 R 3 , wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the NR 2 R 3 group and provided that the oxo group when present is located at a carbon atom a with respect to the NR 2 R 3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R is an aryl or heteroaryl group; and R 2 , R 3 , R 4 and R 5 are as defined in the claims. Also provided are patient packs, pharmaceutical kits and packs and compositions containing the combinations, methods for preparing the combinations and their use in combination therapy as anticancer agents.

  该发明提供了一种组合物，包括一个辅助化合物（例如一个、两个或更多个辅助化合物）和具有蛋白激酶B抑制活性的式（I）化合物：其中A是含有1至7个碳原子的饱和碳氢链连接基团，连接基团在R1和NR2R3之间延伸的最大链长为5个原子，在E和NR2R3之间延伸的最大链长为4个原子，其中连接基团中的一个碳原子可以选择性地被氧原子或氮原子取代；连接基团A的碳原子可以选择性地携带来自酮基、氟和羟基的一个或多个取代基，前提是当羟基存在时，不位于相对于NR2R3基团的碳原子a处，且当酮基存在时，位于相对于NR2R3基团的碳原子a处；E是单环或双环碳环或杂环基团；R是芳基或杂芳基团；R2、R3、R4和R5如权利要求中所定义。还提供了患者包装、药物配套和包装以及含有这些组合物的组合物、制备这些组合物的方法以及它们作为抗癌剂的联合治疗中的用途。
• [EN] FORMYLATED N-HETEROCYCLIC DERIVATIVES AS FGFR4 INHIBITORS<br/>[FR] DÉRIVÉS N-HÉTÉROCYCLIQUES FORMYLÉS UTILISÉS EN TANT QU'INHIBITEURS DE FGFR4
  申请人：NOVARTIS AG

  公开号：WO2016151499A1

  公开（公告）日：2016-09-29

  The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; (I) a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.

  本发明提供了化合物(I)或其药学上可接受的盐；(I)制造该化合物的方法及其治疗用途。本发明还提供了药理活性剂的组合物和包含该化合物的药物组合物。