(2R,3S,4R,5S)-1-(5-(((3R,5R,7R)-adamantan-1-yl)methoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol | 1004320-62-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (2R,3S,4R,5S)-1-(5-(((3R,5R,7R)-adamantan-1-yl)methoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol
• 英文别名: N-[5-(adamantan-1-ylmethoxy)-pentyl]-D-galacto-1-deoxynojirimycin；N-[5-(Adamantan-1-yl-methoxy)-pentyl]-D-galacto-1-deoxynojirimycin；(2R,3S,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol
• CAS: 1004320-62-0
• 化学式: C₂₂H₃₉NO₅
• 分子量: 397.555
• InChiKey: XVYLNHVEAOOEGI-BDEFQLHKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  93.4
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  在 盐酸 、 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 水 为溶剂， 20.0 ℃ 、400.01 kPa 条件下， 反应 20.0h， 以90 mg的产率得到(2R,3S,4R,5S)-1-(5-(((3R,5R,7R)-adamantan-1-yl)methoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol
  参考文献：
  名称：

  Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

  摘要：

  The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action or 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbAlc. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.

  DOI：

  10.1021/jm901281m

文献信息

• A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
  作者：Daniël Lahav、Bing Liu、Richard J. B. H. N. van den Berg、Adrianus M. C. H. van den Nieuwendijk、Tom Wennekes、Amar T. Ghisaidoobe、Imogen Breen、Maria J. Ferraz、Chi-Lin Kuo、Liang Wu、Paul P. Geurink、Huib Ovaa、Gijsbert A. van der Marel、Mario van der Stelt、Rolf G. Boot、Gideon J. Davies、Johannes M. F. G. Aerts、Herman S. Overkleeft

  DOI：10.1021/jacs.7b07352

  日期：2017.10.11

  assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP

  人非溶酶体葡萄糖基神经酰胺酶（GBA2）是控制糖脂水平的几种酶之一，其活性与几种人类疾病状态相关。迫切需要设计或发现选择性的GBA2抑制剂作为化学工具和潜在的治疗剂。在这里，我们描述了基于荧光偏振活性的蛋白质谱分析（FluoPol-ABPP）测定法的发展，该测定法可从350多种亚氨基糖文库中快速鉴定GBA2抑制剂。基于FluoPol-ABPP筛选的线索生成聚焦库，并针对与其他葡糖神经酰胺代谢酶，葡糖神经酰胺合酶（GCS），溶酶体葡糖神经酰胺酶（GBA）和胞质保留β-葡糖苷酶GBA3的GBA2选择性偏移进行评估。我们的工作产生了有效的和选择性的GBA2抑制剂，
• Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation
  作者：Tom Wennekes、Alfred J. Meijer、Albert K. Groen、Rolf G. Boot、Johanna E. Groener、Marco van Eijk、Roelof Ottenhoff、Nora Bijl、Karen Ghauharali、Hang Song、Tom J. O’Shea、Hanlan Liu、Nelson Yew、Diane Copeland、Richard J. van den Berg、Gijsbert A. van der Marel、Herman S. Overkleeft、Johannes M. Aerts

  DOI：10.1021/jm901281m

  日期：2010.1.28

  The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action or 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbAlc. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.