(S)-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl) 1-(3,3-dimethyl-2-oxopentanoyl)pyrrolidine-2-carboxylate | 1374118-98-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: (S)-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl) 1-(3,3-dimethyl-2-oxopentanoyl)pyrrolidine-2-carboxylate
• 英文别名: [(1R)-3-(3,4-dimethoxyphenyl)-1-[3-(2-morpholin-4-ylethoxy)phenyl]propyl] (2S)-1-(3,3-dimethyl-2-oxopentanoyl)pyrrolidine-2-carboxylate
• CAS: 1374118-98-5
• 化学式: C₃₅H₄₈N₂O₈
• 分子量: 624.775
• InChiKey: OQDIIFAIGYOVNP-URLMMPGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  45
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-(E)-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 、 lithium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 (S)-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl) 1-(3,3-dimethyl-2-oxopentanoyl)pyrrolidine-2-carboxylate
  参考文献：
  名称：

  Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52

  摘要：

  The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, 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 that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.

  DOI：

  10.1021/jm201746x

文献信息

• Pipecolate-diketoamides for treatment of psychiatric disorders
  申请人：Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.

  公开号：EP2607352A1

  公开（公告）日：2013-06-26

  The present invention relates to compounds having a pipecolate diketoamide scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said pipecolate diketoamide compounds can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.

  本发明涉及具有吡啶甲酸二酮酰胺骨架的化合物，这些化合物的药用盐以及含有至少一种这些化合物的药物组合物，与药用载体、赋形剂和/或稀释剂一起。所述的吡啶甲酸二酮酰胺化合物可用于预防和/或治疗精神障碍和神经退行性疾病、障碍和症状。
• Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52
  作者：Ranganath Gopalakrishnan、Christian Kozany、Steffen Gaali、Christoph Kress、Bastiaan Hoogeland、Andreas Bracher、Felix Hausch

  DOI：10.1021/jm201746x

  日期：2012.5.10

  The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, 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 that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.