(S)-2-(3,4-dimethoxyphenoxy)ethyl 1-(benzo[d]thiazol-6-ylsulfonyl)piperidine-2-carboxylate | 1373829-78-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-(3,4-dimethoxyphenoxy)ethyl 1-(benzo[d]thiazol-6-ylsulfonyl)piperidine-2-carboxylate
• 英文别名: 2-(3,4-dimethoxyphenoxy)ethyl (S)-1-(benzo[d]thiazol-6-ylsulfonyl)piperidine-2-carboxylate；2-(3,4-dimethoxyphenoxy)ethyl (2S)-1-(1,3-benzothiazol-6-ylsulfonyl)piperidine-2-carboxylate
• CAS: 1373829-78-7
• 化学式: C₂₃H₂₆N₂O₇S₂
• 分子量: 506.601
• InChiKey: WMMCUKFDSUJWAI-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  141
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-Boc-L-哌啶-2-羧酸 在 potassium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 2.0h， 生成 (S)-2-(3,4-dimethoxyphenoxy)ethyl 1-(benzo[d]thiazol-6-ylsulfonyl)piperidine-2-carboxylate
  参考文献：
  名称：

  Increasing the Efficiency of Ligands for FK506-Binding Protein 51 by Conformational Control

  摘要：

  The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.

  DOI：

  10.1021/jm400087k

文献信息

• Exploration of Pipecolate Sulfonamides as Binders of the FK506-Binding Proteins 51 and 52
  作者：Ranganath Gopalakrishnan、Christian Kozany、Yansong Wang、Sabine Schneider、Bastiaan Hoogeland、Andreas Bracher、Felix Hausch

  DOI：10.1021/jm201747c

  日期：2012.5.10

  the signal transduction of steroid hormone receptors. Single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products, which tightly bind to most FKBP family members, including FKBP51 and FKBP52. A bioisosteric replacement of the α-ketoamide moiety of rapamycin and FK506 with a sulfonamide

  FK506结合蛋白（FKBP）51和52是可调节类固醇激素受体信号转导的伴侣蛋白。编码FKBP51的基因中的单核苷酸多态性已与多种精神疾病有关。雷帕霉素和FK506是两个大环天然产物，它们与大多数FKBP家族成员紧密结合，包括FKBP51和FKBP52。考虑到保留保守的氢键，用磺酰胺对雷帕霉素和FK506的α-酮酰胺部分进行生物等位取代。重点研究了基于固体支持物的合成方案，该方案导致对FKBP51和FKBP52具有亚微摩尔亲和力的配体。一种磺酰胺类似物的分子结合模式通过X射线晶体学证实。
• Increasing the Efficiency of Ligands for FK506-Binding Protein 51 by Conformational Control
  作者：Yansong Wang、Alexander Kirschner、Anne-Katrin Fabian、Ranganath Gopalakrishnan、Christoph Kress、Bastiaan Hoogeland、Uwe Koch、Christian Kozany、Andreas Bracher、Felix Hausch

  DOI：10.1021/jm400087k

  日期：2013.5.23

  The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.