ethyl 1-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate | 931313-57-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: ethyl 1-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
• 英文别名: ethyl N-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate；ethyl 1-benzyl-6-fluoro-4-oxoquinoline-3-carboxylate
• CAS: 931313-57-4
• 化学式: C₁₉H₁₆FNO₃
• mdl: MFCD08540129
• 分子量: 325.339
• InChiKey: HYIVPDNUXHHFOV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 1-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 在 盐酸 、 水 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 4.25h， 生成 N,1-dibenzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide
  参考文献：
  名称：

  4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  DOI：

  10.1016/j.bmc.2014.05.028
• 作为产物：
  描述：

  2,5-二氟苯甲酸 在 氯化亚砜 、 potassium carbonate 、 三乙胺 作用下， 以 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 5.67h， 生成 ethyl 1-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
  参考文献：
  名称：

  4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  DOI：

  10.1016/j.bmc.2014.05.028

文献信息

• FRET Studies of Quinolone-Based Bitopic Ligands and Their Structural Analogues at the Muscarinic M₁ Receptor
  作者：Regina Messerer、Michael Kauk、Daniela Volpato、Maria Consuelo Alonso Canizal、Jessika Klöckner、Ulrike Zabel、Susanne Nuber、Carsten Hoffmann、Ulrike Holzgrabe

  DOI：10.1021/acschembio.6b00828

  日期：2017.3.17

  partial agonists as well as allosteric modulators for the M1 muscarinic acetylcholine (M1AChR) receptor, two different series of bipharmacophoric ligands and their structural analogues were designed and synthesized. The hybrids were composed of the benzyl quinolone carboxylic acid (BQCA)-derived subtype selective allosteric modulator 3 and the orthosteric building block 4-((4,5-dihydroisoxazol-3-yl)oxy)-N

  为了设计M 1毒蕈碱型乙酰胆碱（M 1 AChR）受体的部分激动剂和变构调节剂，设计并合成了两个不同系列的双药效配体及其结构类似物。杂种由苄基喹诺酮羧酸（BQCA）衍生的亚型选择性变构调节剂3和正构构筑物4-（（4,5-dihydroisoxazol-3-yl）oxy）-N，N-methylbut-2-组成分别是yn-1-胺（petrorox的碱）1或内源性配体2-（二甲基氨基）乙酸乙酯（乙酰胆碱的碱）2。这两个药效团通过不同长度（C4，C6，C8和C10）的亚烷基链。此外，1和2以及修饰的BQCA 3的相应结构类似物研究了在C2和C10之间具有不同烷基链长度的化合物。为了了解这些化合物如何在分子水平上与G蛋白偶联受体（GPCR）相互作用以及单个部分如何促进配体受体相互作用，研究了在活的单细胞系统中进行的荧光共振能量转移（FRET）测量。修饰的正构配体的表征表明，连接至正构的连接基迅速减弱
• Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates
  作者：Joel K. Annor-Gyamfi、Ebenezer Ametsetor、Kevin Meraz、Richard A. Bunce

  DOI：10.3390/molecules26040890

  日期：——

  developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement

  在50-90°C下，使用Morita-Baylis-Hillman（MBH）乙酸酯与伯脂肪族和芳香族胺在DMF中的多米诺反应，已经开发出一种有效的合成途径，以取代高度取代的二氢喹啉和二氢萘啶。MBH底物包含与丙烯酸酯或丙烯腈aza-Michael受体相邻的侧链乙酸酯，以及朝S N Ar环闭合活化的芳环。对照实验确定，初始反应是胺对侧链乙酸酯的S N 2'型置换，以生成烯烃产物，其中所添加的氮亲核试剂位于S NAr芳环受体。因此，在环化之前需要平衡初始烯烃的几何形状。从具有侧链丙烯腈部分的底物靶向二氢萘吡啶的几个反应中观察到进一步的双键迁移。发现在这些环状物中结合有2，5-二氟苯基部分的MBH乙酸酯具有双重反应性。在不存在O 2的情况下，形成了预期的二氢喹啉，而在存在O 2的情况下，生成了喹诺酮。分离出的所有产品均具有良好至极好的收率（72–93％）。报告了许多案例（42），并讨论了机制。
• Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor
  作者：Xinyu Chen、Jessika Klöckner、Janine Holze、Cornelia Zimmermann、Wiebke K. Seemann、Ramona Schrage、Andreas Bock、Klaus Mohr、Christian Tränkle、Ulrike Holzgrabe、Michael Decker

  DOI：10.1021/jm500860w

  日期：2015.1.22

  Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M-1-receptor (hM(1)) with respect to receptor binding and G(q)-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M-1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M-1 receptors to design partial agonists with graded efficacy.
• 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
  作者：Ying Zhi、Li-Xin Gao、Yi Jin、Chun-Lan Tang、Jing-Ya Li、Jia Li、Ya-Qiu Long

  DOI：10.1016/j.bmc.2014.05.028

  日期：2014.7

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.