ethyl 6-(3-aminoazetidin-1-yl)-5-cyano-2-methylnicotinate | 919354-18-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ethyl 6-(3-aminoazetidin-1-yl)-5-cyano-2-methylnicotinate
• 英文别名: ethyl 6-(3-aminoazetidin-1-yl)-5-cyano-2-methylpyridine-3-carboxylate
• CAS: 919354-18-0
• 化学式: C₁₃H₁₆N₄O₂
• 分子量: 260.296
• InChiKey: JODJYHYAUPEJJU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  92.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 6-(3-aminoazetidin-1-yl)-5-cyano-2-methylnicotinate 、 异氰酸苯磺酰酯 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以0.224 g的产率得到N-(1-(3-cyano-5-(ethoxy(methoxy)methyl)-6-methylpyridin-2-yl)azetidin-3-ylcarbamoyl)benzenesulfonamide
  参考文献：
  名称：

  Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor

  摘要：

  The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility <0.1 mu M, microsomal CLint (HLM) >= 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.007
• 作为产物：
  描述：

  5-氰基-1,6-二氢-2-甲基-6-氧代-3-吡啶羧酸乙酯 在 盐酸 、 草酰氯 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 35.0h， 生成 ethyl 6-(3-aminoazetidin-1-yl)-5-cyano-2-methylnicotinate
  参考文献：
  名称：

  Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor

  摘要：

  The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility <0.1 mu M, microsomal CLint (HLM) >= 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.007

文献信息

• Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state
  作者：Alessandro Villa、Barbara Klein、Bieneke Janssen、Jordi Pedragosa、Giovanna Pepe、Bastian Zinnhardt、Danielle J. Vugts、Paolo Gelosa、Luigi Sironi、Wissam Beaino、Annelaure Damont、Frédéric Dollé、Benoit Jego、Alexandra Winkeler、Dieter Ory、Olof Solin、Johnny Vercouillie、Uta Funke、Sandra Laner-Plamberger、Linda V. Blomster、Palle Christophersen、Elisabetta Vegeto、Ludwig Aigner、Andreas Jacobs、Anna M. Planas、Adriana Maggi、Albert D. Windhorst

  DOI：10.7150/thno.25572

  日期：——

  Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers.

  小胶质细胞是影响中枢神经系统的神经疾病和神经退行性疾病治疗干预的潜在靶点。为了评估旨在减少小胶质细胞损伤组织活动和/或促进这些细胞保护潜力的疗法的有效性，需要合适的临床前和临床工具来进行小胶质细胞活动和动态的体内分析。本研究的目标是识别小胶质细胞抗炎/保护状态的新转化标记物，以便开发新的PET示踪剂。
• Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor
  作者：Peter Bach、Jonas Boström、Kay Brickmann、J.J.J. van Giezen、Robert D. Groneberg、Darren M. Harvey、Michael O'Sullivan、Fredrik Zetterberg

  DOI：10.1016/j.ejmech.2013.04.007

  日期：2013.7

  The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility <0.1 mu M, microsomal CLint (HLM) >= 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.