(2R,3S,4R,5S)-1-丁基-2-(羟基甲基)-3,4,5-哌啶三醇 | 141206-42-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: (2R,3S,4R,5S)-1-丁基-2-(羟基甲基)-3,4,5-哌啶三醇
• 中文别名: 2-二甲氨基-5-苯基二氮烯基-苯-1,3-二磺酸；N-(正丁基)脱氧半乳糖霉素；N -(正丁基)脱氧半乳糖霉素
• 英文名称: N-butyl-D-galacto-1-deoxynojirimycin
• 英文别名: N-butyldeoxygalactonojirimycin；NB-DGJ；(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol；lucerastat；N-butyl-1-deoxygalactonojirimycin；N-(n-butyl)deoxygalactonojirimycin；ACT-434964
• CAS: 141206-42-0
• 化学式: C₁₀H₂₁NO₄
• 分子量: 219.281
• InChiKey: UQRORFVVSGFNRO-XFWSIPNHSA-N

物化性质

• 熔点：
  123-124°C
• 沸点：
  394.7±42.0 °C(Predicted)
• 密度：
  1.234±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：20mg/mL；二甲基亚砜：30mg/mL；乙醇：5mg/mL； PBS（pH 7.2）：10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  84.2
• 氢给体数：
  4
• 氢受体数：
  5

安全信息

• 储存条件：
  存储条件：2-8°C，需密封并置于干燥处。

制备方法与用途

生物活性

Lucerastat 是 Miglustat 的半乳糖形式，是口服活性的葡萄糖酰神经酰胺合成酶 (GCS) 抑制剂。Lucerastat 在 Fabry 疾病研究中具有潜在应用价值。

体外研究

Fabry 患者衍生的成纤维细胞（基因型：R301G（残余 -GalA 活性；20%）, R220X（<3%）和 W162X（<1%）），用于实验。

细胞活力测定

参数	详情
细胞系	Fabry 患者衍生的成纤维细胞，基因型：R301G, R220X 和 W162X
浓度	-
孵化时间	9 天
结果	剂量依赖性地抑制 GCS，减少甘油神经酰胺并增加鞘磷脂。

体内研究

Lucerastat（1200 mg/kg/日饲料混匀），作为 GCS 抑制剂，在无残余 -GalA 活性的条件下减少体内 Gb3 含量。

动物模型

参数	详情
动物模型	Fabry 小鼠（Gla-/0 和 Gla-/-，每种性别各5或6只）
剂量	1200 mg/kg/日饲料混匀
给药途径	饲料混匀共给药20周
结果	在两个主要受 FD 影响的器官中减少脂质储存：肾脏平均 Gb3 (-33%，p<0.01) 和背根神经节中的 α-半乳糖终止的鞘糖苷脂（-48%，p<0.05）。在 Fabry 小鼠肝脏中，甘油神经酰胺 (24:0) 减少 (-59%，p<0.001)，Gb3(24:1) (-37%，p<0.05)，证明通过 GCS 抑制减少了底物。

反应信息

• 作为反应物：
  描述：

  阿司匹林 、 (2R,3S,4R,5S)-1-丁基-2-(羟基甲基)-3,4,5-哌啶三醇 以 乙腈 为溶剂， 反应 67.5h， 生成 lucerastat O-acetylsalicylic acid salt
  参考文献：
  名称：

  [EN] SOLID STATE FORMS OF LUCERASTAT SALTS AND PROCESS FOR PREPARATION THEREOF
  [FR] FORMES À L'ÉTAT SOLIDE DE SELS DE LUCÉRASTAT ET LEUR PROCÉDÉ DE PRÉPARATION

  摘要：

  本公开涉及Lucerastat的固态形式，在某些实施例中为结晶态Lucerastat：L-焦谷氨酸，结晶态Lucerastat：水杨酸，结晶态Lucerastat：富马酸，结晶态Lucerastat：苯甲酸和结晶态Lucerastat：邻乙酰水杨酸，其固态形式，其制备过程，以及由此构成的药物组合物。

  公开号：

  WO2021061701A1
• 作为产物：
  描述：

  (2R,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-butylpiperidine 在 palladium dichloride 氢气 作用下， 以 甲醇 为溶剂， 反应 12.0h， 生成 (2R,3S,4R,5S)-1-丁基-2-(羟基甲基)-3,4,5-哌啶三醇
  参考文献：
  名称：

  [EN] PROCESS FOR PRODUCTION OF DEOXYGALACTONOJIRIMYCIN DERIVATIVES
  [FR] PROCEDE DE PRODUCTION DE DERIVES DE DESOXYGALACTONOJIRIMYCINE

  摘要：

  一种生产N-取代脱氧半乳糖酰胺衍生物的过程，包括还原环闭合，然后去保护。

  公开号：

  WO2004054975A1

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，
• [EN] CRYSTALLINE FORM OF N-BUTYLDEOXYGALACTONOJIRIMYCIN<br/>[FR] FORME CRISTALLINE DE N-BUTYLDÉOXYGALACTONOJIRIMYCINE
  申请人：IDORSIA PHARMACEUTICALS LTD

  公开号：WO2018220131A1

  公开（公告）日：2018-12-06

  The invention relates to a crystalline form of [(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)-piperidine-3,4,5-triol, processes for the preparation thereof, pharmaceutical compositions containing such a crystalline form, and its use as a medicament, especially as glycolipid biosynthesis inhibitor.

  该发明涉及[(2R,3S,4R,5S)-1-丁基-2-(羟甲基)-哌啶-3,4,5-三醇的晶体形式，其制备方法，含有该晶体形式的药物组成物，以及其作为药物的用途，特别是作为糖脂生物合成抑制剂。
• Use of alkylated iminosugars to treat multidrug resistance
  申请人：G.D. Searle & Company

  公开号：US06225325B1

  公开（公告）日：2001-05-01

  Methods and compositions for preventing, reducing, or reversing multidrug resistance (MDR) during cancer chemotherapy in patients undergoing treatment with therapeutically effective amounts of chemotherapeutic agents are provided. The methods comprise administering an anti-MDR effective amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol or galactitol iminosugar to a patient.

  本发明提供了在接受治疗有效量的化疗药物治疗的癌症患者中预防、减少或逆转多药耐药（MDR）的方法和组合物。该方法包括向患者给予抗-MDR有效量的N-取代-1,5-二脱氧-1,5-亚胺-D-葡萄糖醇或半乳糖醇亚胺糖。
• 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.
• 2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease
  作者：Atsushi Kato、Yukiko Yamashita、Shinpei Nakagawa、Yuriko Koike、Isao Adachi、Jackie Hollinshead、Robert J. Nash、Kyoko Ikeda、Naoki Asano

  DOI：10.1016/j.bmc.2010.04.048

  日期：2010.6.1

  Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-D-altritol (DIA) (2), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-D-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5 mu M. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3 days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme. (C) 2010 Elsevier Ltd. All rights reserved.