1-Benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid | 1338665-48-7

• 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: 1-Benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
• 英文别名: 1-benzyl-6-fluoro-4-oxoquinoline-3-carboxylic acid
• CAS: 1338665-48-7
• 化学式: C₁₇H₁₂FNO₃
• mdl: MFCD25952863
• 分子量: 297.286
• InChiKey: KTTRQAGYEPRIHE-UHFFFAOYSA-N

物化性质

• 熔点：
  237-239 °C
• 沸点：
  479.6±45.0 °C(Predicted)
• 密度：
  1.416±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-Benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 、 苄胺 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.25h， 以63%的产率得到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 盐酸 、 氯化亚砜 、 水 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 7.67h， 生成 1-Benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  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

• A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy
  作者：Luca Agnetta、Michael Kauk、Maria Consuelo Alonso Canizal、Regina Messerer、Ulrike Holzgrabe、Carsten Hoffmann、Michael Decker

  DOI：10.1002/anie.201701524

  日期：2017.6.12

  synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M1 receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated

  尽管总体上M受体和GPCR具有巨大的治疗意义，但对G蛋白偶联受体（GPCR）尤其是毒蕈碱型乙酰胆碱（mACh或M）受体激活的方式和时程的研究仍处于起步阶段。 。我们在本文中使用了双立体配体，该配体可以与直立的同时与神经递质，结合位点和变构的配体相互作用。我们合成了一个可光开关的（光致变色）偶氮苯部分。我们表征了这种称为BQCAAI的配体的光物理性质，并通过一套FRET技术在M 1处研究了其作为药理学工具化合物的适用性。受体。BQCAAI被证明是前所未有的分子工具。它是第一个可光转换的双空间配体，其活性可以受光调节。我们还应用了BQCCAI来研究几种受体激活过程的时间过程。
• 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
• 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.