2(S)-[[5-[3-[2-[tert-butyl(dimethyl)silanyloxy]ethyl]-5-isoxazolyl]-pyridin-3-yloxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester | 1404372-54-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2(S)-[[5-[3-[2-[tert-butyl(dimethyl)silanyloxy]ethyl]-5-isoxazolyl]-pyridin-3-yloxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (2S)-2-[[5-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,2-oxazol-5-yl]pyridin-3-yl]oxymethyl]pyrrolidine-1-carboxylate
• CAS: 1404372-54-8
• 化学式: C₂₆H₄₁N₃O₅Si
• 分子量: 503.714
• InChiKey: WHAUTNZBCYMMDH-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.08
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  86.9
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2(S)-[[5-[3-[2-[tert-butyl(dimethyl)silanyloxy]ethyl]-5-isoxazolyl]-pyridin-3-yloxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester 在 4-二甲氨基吡啶 、 四丁基氟化铵 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 5.5h， 生成 ethylcarbamic acid 2-[5-[5-(2(S)-pyrrolidinylmethoxy)-3-pyridinyl]-3-isoxazolyl]ethyl ester trifluoroacetate
  参考文献：
  名称：

  Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II

  摘要：

  In our continued efforts to develop alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certam isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [H-3]epibatidine binding studies together with functional assays based on Rb-86(+) ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.

  DOI：

  10.1021/jm301177j
• 作为产物：
  描述：

  2(S)-[(5-ethynylpyridin-3-yloxy)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester 、 tert-butyl(dimethyl)(3-nitropropoxy)silane 在 异氰酸苯酯 、 三乙胺 作用下， 以 甲苯 为溶剂， 生成 2(S)-[[5-[3-[2-[tert-butyl(dimethyl)silanyloxy]ethyl]-5-isoxazolyl]-pyridin-3-yloxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II

  摘要：

  In our continued efforts to develop alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certam isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [H-3]epibatidine binding studies together with functional assays based on Rb-86(+) ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.

  DOI：

  10.1021/jm301177j

文献信息

• Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II
  作者：Li-Fang Yu、J. Brek Eaton、Allison Fedolak、Han-Kun Zhang、Taleen Hanania、Dani Brunner、Ronald J. Lukas、Alan P. Kozikowski

  DOI：10.1021/jm301177j

  日期：2012.11.26

  In our continued efforts to develop alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certam isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [H-3]epibatidine binding studies together with functional assays based on Rb-86(+) ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.