N-[5-((3’,4’-O-methylene-3’,4’-bishydroxy)[1,1’-biphenyl]-4-yl)methoxypentyl]-1-deoxynojirimycin

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: N-[5-((3’,4’-O-methylene-3’,4’-bishydroxy)[1,1’-biphenyl]-4-yl)methoxypentyl]-1-deoxynojirimycin
• 英文别名: (2R,3R,4R,5S)-1-(5-((4-(benzo[d][1,3]dioxol-5-yl)benzyl)oxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol；(2R,3R,4R,5S)-1-[5-[[4-(1,3-benzodioxol-5-yl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol
• 化学式: C₂₅H₃₃NO₇
• 分子量: 459.54
• InChiKey: CJZGTRIZBSILBI-RRJCBXKSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-[(苄氧基)甲基]哌啶 在 盐酸 、 palladium on carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 70.0 ℃ 、400.01 kPa 条件下， 反应 24.0h， 生成 N-[5-((3’,4’-O-methylene-3’,4’-bishydroxy)[1,1’-biphenyl]-4-yl)methoxypentyl]-1-deoxynojirimycin
  参考文献：
  名称：

  基于荧光偏振活性的蛋白质谱分析法在人类非溶酶体葡萄糖基神经酰胺酶的有效，选择性抑制剂的发现中。

  摘要：

  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，

  DOI：

  10.1021/jacs.7b07352

文献信息

• N-(5-((aryl or heteroaryl)methyloxy)pentyl)-substituted iminosugars as inhibitors of glucosylceramide synthase
  申请人：ACADEMISCH MEDISCH CENTRUM

  公开号：US10189784B2

  公开（公告）日：2019-01-29

  Deoxynojirimycin and deoxygalactonojirimycin derivatives according to the present invention are N-alkylated D-galacto, D-gluco- or L-ido-deoxynojirimycin with a linear methyloxypentyl group bearing various sidegroups and a non-fused bicyclic aromatic group (“X”) on the methyloxy-carbon. These compounds display an increased inhibitory potency towards GCS, and/or an increased inhibitory potency towards GBA2, and/or a decreased inhibitory potency towards GBA1, relative to known deoxynojirimycin derivatives of the same (D-gluco, L-ido or D-galacto) configuration. Therefore, compounds of the present invention are effective in the treatment of diseases which are associated with an irregular level of cytosolic or lysosomal glucosylceramide and/or higher glycosphingolipids, such as a lysosomal storage disorder, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, Sialidosis, Niemann Pick disease type C and AMRF, or a symptom of one of the diseases collectively classed as metabolic syndrome, such as obesity, insulin resistance, hyperlipidemia, hypercholesterolemia, polycystic kidney disease, type II diabetes and chronic inflammation, or a neurodenegerative disorder, such as Parkinson disease or Lewy-body dementia.

  根据本发明，脱氧野尻霉素和脱氧半乳糖苷霉素衍生物是N-烷基化的D-半乳糖苷、D-葡萄糖苷或L-同位脱氧野尻霉素，其甲基氧基碳上有一个带有各种侧基的线性甲基氧基戊基和一个未融合的双环芳香基团（"X"）。与已知的相同（D-葡萄糖基、L-氨基或 D-半乳糖基）构型的脱氧野尻霉素衍生物相比，这些化合物对 GCS 的抑制效力增强，和/或对 GBA2 的抑制效力增强，和/或对 GBA1 的抑制效力减弱。因此，本发明的化合物可有效治疗与细胞膜或溶酶体葡萄糖甘油酰胺和/或高级糖磷脂的不规则水平有关的疾病，如溶酶体贮积症，如戈谢病、法布里病、泰-萨克斯病、桑霍夫病、GM1 神经节苷脂病、Sialidosis、Niemann 病、GM2 神经节苷脂病、GM3 神经节苷脂病等、胰岛素抵抗、高脂血症、高胆固醇血症、多囊肾、II 型糖尿病和慢性炎症等疾病的症状，或帕金森病或路易体痴呆等神经系统疾病的症状。
• Identification and Development of Biphenyl Substituted Iminosugars as Improved Dual Glucosylceramide Synthase/Neutral Glucosylceramidase Inhibitors
  作者：Amar T. Ghisaidoobe、Richard J. B. H. N. van den Berg、Saleem S. Butt、Anneke Strijland、Wilma E. Donker-Koopman、Saskia Scheij、Adrianus M. C. H. van den Nieuwendijk、Gerrit-Jan Koomen、Arnold van Loevezijn、Mark Leemhuis、Tom Wennekes、Mario van der Stelt、Gijsbert A. van der Marel、Constant A. A. van Boeckel、Johannes M. F. G. Aerts、Herman S. Overkleeft

  DOI：10.1021/jm501181z

  日期：2014.11.13

  This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.
• N-(5-(BIPHEN-4-YLMETHYLOXY)PENTYL)-SUBSTITUTED IMINOSUGARS AS INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE
  申请人：Academisch Medisch Centrum

  公开号：EP3461812B1

  公开（公告）日：2021-10-13
• N-(5-((ARYL OR HETEROARYL)METHYLOXY)PENTYL)-SUBSTITUTED IMINOSUGARS AS INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE
  申请人：ACADEMISCH MEDISCH CENTRUM

  公开号：US20170226058A1

  公开（公告）日：2017-08-10

  Deoxynojirimycin and deoxygalactonojirimycin derivatives according to the present invention are N-alkylated D-galacto, D-gluco- or L-ido-deoxynojirimycin with a linear methyloxypentyl group bearing various sidegroups and a non-fused bicyclic aromatic group (“X”) on the methyloxy-carbon. These compounds display an increased inhibitory potency towards GCS, and/or an increased inhibitory potency towards GBA2, and/or a decreased inhibitory potency towards GBA1, relative to known deoxynojirimycin derivatives of the same (D-gluco, L-ido or D-galacto) configuration. Therefore, compounds of the present invention are effective in the treatment of diseases which are associated with an irregular level of cytosolic or lysosomal glucosylceramide and/or higher glycosphingolipids, such as a lysosomal storage disorder, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, Sialidosis, Niemann Pick disease type C and AMRF, or a symptom of one of the diseases collectively classed as metabolic syndrome, such as obesity, insulin resistance, hyperlipidemia, hypercholesterolemia, polycystic kidney disease, type II diabetes and chronic inflammation, or a neurodenegerative disorder, such as Parkinson disease or Lewy-body dementia.