米加司他 | 108147-54-2

• 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: 米加司他
• 英文名称: 1-deoxygalactonojirimycin
• 英文别名: Migalastat；DGJ；1-deoxygalactostatin；(2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol
• CAS: 108147-54-2
• 化学式: C₆H₁₃NO₄
• 分子量: 163.174
• InChiKey: LXBIFEVIBLOUGU-DPYQTVNSSA-N

物化性质

• 熔点：
  243-245 °C
• 沸点：
  361.1±42.0 °C(Predicted)
• 密度：
  1.456±0.06 g/cm3(Predicted)
• 稳定性/保质期：
  遵照规定使用和储存，则不会发生分解。

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  93
• 氢给体数：
  5
• 氢受体数：
  5

ADMET

代谢

基于体内数据，米加司他是一种尿苷二磷酸葡萄糖醛酸基转移酶（也称为UGT或UDPGT）的底物，是一种次要的消除途径。米加司他在体外不是P-糖蛋白（P-gP）的底物，且认为米加司他不太可能受到与细胞色素P450s的药物-药物相互作用的 影响。在一项健康男性志愿者进行的150毫克[14C]-米加司他盐酸的药代动力学试验中，发现血浆中回收的放射性标记剂量的99%由未改变的米加司他（77%）和3种去氢化的O-葡萄糖醛酸苷结合代谢物M1、M2和M3（13%）组成。大约9%的总放射性未被归属。

Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (otherwise known as UGT or UDPGT), being a minor elimination pathway. Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro and it is considered unlikely that migalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat HCl revealed that 99% of the radiolabeled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1, M2, and M3 (13%). Approximately 9% of the total radioactivity was unassigned.

来源:DrugBank

毒理性

• 肝毒性

在安慰剂对照试验中，肝功能测试异常是罕见的，使用米加司他汀与安慰剂治疗相比并不更常见。出现的异常都是轻微的，并且在不中断用药的情况下自发解决。在这些上市前临床试验以及更广泛的临床应用以来，没有报告过归因于米加司他汀的急性肝损伤伴黄疸的病例。然而，其使用的总临床经验还是有限的。

In placebo-controlled trials, liver test abnormalities were rare and no more common with migalastat than with placebo treatment. What abnormalities occurred were mild and resolved spontaneously without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to migalastat. However, the total clinical experience with its use has been limited.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于在哺乳期间使用米加斯塔的信息。由于没有关于在哺乳期间使用米加斯塔的信息，因此应谨慎使用，特别是在哺乳新生儿或早产儿时。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of migalastat during breastfeeding. Because no information is available on the use of migalastat during breastfeeding caution should be used, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

在1至100微摩尔浓度范围内给予[14C]- migalastat盐酸后，未检测到可察觉的血浆蛋白结合。

There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 uM.

来源:DrugBank

吸收、分配和排泄

• 吸收

在肠道吸收为主的情况下，单次口服150毫克米加司他汀盐酸盐或单次2小时150毫克静脉输注的绝对生物利用度（AUC）大约为75%。在单次口服150毫克米加司他汀盐酸盐溶液后，达到最高血浆浓度的时间大约为3小时。在米加司他汀盐酸盐口服剂量从50毫克到1,250毫克范围内，血浆米加司他汀暴露量（AUC0-∞）和Cmax呈剂量比例增加。与禁食状态相比，高脂肪餐时服用米加司他汀，或在高脂肪餐前1小时或轻餐后1小时服用米加司他汀，会导致总米加司他汀暴露量（AUC0-∞）平均降低37%至42%，峰值米加司他汀暴露量（Cmax）平均降低15%至40%。

With absorption occurring largely in the gut, the absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75%. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg. Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC0-∞) and reductions of 15% to 40% in mean peak migalastat exposure (Cmax) compared with the fasting state.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在健康男性志愿者中进行的150毫克[14C]- migalastat盐酸的药代动力学试验显示，大约77%和20%的放射性标记剂量分别通过尿液回收和在粪便中排泄。

A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% and 20% of the radiolabeled dose was recovered in urine and excreted in the feces, respectively.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在健康志愿者中，米加司他汀（migalastat）在单次口服递增剂量（25-675 mg 米加司他汀 HCl）后的分布容积（Vz/F）范围为77至133升，表明它能够很好地分布到组织中，并且大于总体水含量（42升）。

In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) ranged from 77 to 133 L, indicating it is well distributed into tissues and greater than total body water (42 liters).

来源:DrugBank

吸收、分配和排泄

• 清除

在给予单次口服剂量（25-675毫克米加司他汀盐酸盐）后，清除率（CL/F）没有发现趋势。在150毫克剂量下，CL/F大约为11到14升/小时。

Following ascending single oral doses (25-675 mg migalastat hydrochloride), no trends were found for clearance, CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr.

来源:DrugBank

安全信息

• 危险品标志：
  Xi
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 安全说明：
  S26,S36
• 储存条件：
  存储于2-8℃阴凉干燥处

制备方法与用途

migalastat（GR181413A，游离碱）是一种口服的α-半乳糖苷酶A(α-Gal A)活性和竞争性抑制剂，其对人α-Gal A的IC50值为0.04μM。

反应信息

• 作为反应物：
  描述：

  米加司他 在 盐酸 作用下， 以 水 为溶剂， 生成 (2R,3S,4R,5S)-2-甲醇哌啶-3,4,5-三醇盐酸盐
  参考文献：
  名称：

  Gluconobacter mediated synthesis of amino sugars

  摘要：

  DOI：

  10.1016/j.molcatb.2014.12.003
• 作为产物：
  描述：

  1-脱氧野尻霉素 在 palladium on activated charcoal 盐酸 、 barium dihydroxide 、 sodium hydroxide 、 氢气 、 sodium hydride 、 碳酸氢钠 、 potassium carbonate 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 10.0~100.0 ℃ 、350.0 kPa 条件下， 反应 163.0h， 生成 米加司他
  参考文献：
  名称：

  Synthesis of d-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-d-galactitol) starting from 1-deoxynojirimycin

  摘要：

  DOI：

  10.1016/0008-6215(90)80031-w

文献信息

• On the Asymmetric Induction in Proline-Catalyzed Aldol Reactions: Reagent-Controlled Addition Reactions of 2,2-Dimethyl-1,3-dioxane-5-one to Acyclic Chiral α-Branched Aldehydes
  作者：Jasna Marjanovic Trajkovic、Vesna Milanovic、Zorana Ferjancic、Radomir N. Saicic

  DOI：10.1002/ejoc.201701073

  日期：2017.11.9

  Proline-catalyzed aldol addition reactions of 2,2-dimethyl-1,3-dioxane-5-one to chiral aldehydes proceed under reagent stereocontrol (in both matched and mismatched cases) if aldehyde α-oxy or α-amino substituents are acyclic. For cyclic substituents, the stereochemical outcome of the aldolization in mismatched cases is difficult to predict.

  如果醛的α-氧基或α-氨基取代基是无环的，则在试剂立体控制下（在匹配和不匹配的情况下），脯氨酸催化的2，2-二甲基-1，3-二恶烷-5-酮与手性醛的羟醛加成反应。对于环状取代基，在不匹配的情况下醛醇缩合的立体化学结果很难预测。
• Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors
  作者：Georg Schitter、Elisabeth Scheucher、Andreas J Steiner、Arnold E Stütz、Martin Thonhofer、Chris A Tarling、Stephen G Withers、Jacqueline Wicki、Katrin Fantur、Eduard Paschke、Don J Mahuran、Brigitte A Rigat、Michael Tropak、Tanja M Wrodnigg

  DOI：10.3762/bjoc.6.21

  日期：——

  N-Alkylation at the ring nitrogen of the D-galactosidase inhibitor 1-deoxygalactonojirimycin with a functionalised C₆ alkyl chain followed by modification with different aromatic substituents provided lipophilic 1-deoxygalactonojirimycin derivatives which exhibit inhibitory properties against β-glycosidases from E. coli and Agrobacterium sp. as well as green coffee bean α-galactosidase. In preliminary studies, these compounds also showed potential as chemical chaperones for GM1-gangliosidosis related β-galactosidase mutants.

  将D-半乳糖苷酶抑制剂1-去氧半乳糖酮基脲的环氮原子进行N-烷基化，接着用不同芳香基团进行修饰，得到了亲脂性的1-去氧半乳糖酮基脲衍生物，这些衍生物对大肠杆菌和根瘤菌β-葡萄糖苷酶以及绿咖啡豆α-半乳糖苷酶具有抑制作用。在初步研究中，这些化合物还显示出潜力作为GM1-神经节苷脂病相关β-半乳糖苷酶突变体的化学伴侣。
• Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors
  作者：Richard J. B. H. N. van den Berg、Erwin R. van Rijssel、Maria Joao Ferraz、Judith Houben、Anneke Strijland、Wilma E. Donker-Koopman、Tom Wennekes、Kimberly M. Bonger、Amar B. T. Ghisaidoobe、Sascha Hoogendoorn、Gijsbert A. van der Marel、Jeroen D. C. Codée、Herman S. Overkleeft、Johannes M. F. G. Aerts

  DOI：10.1002/cmdc.201500407

  日期：2015.12

  in glucosylceramide metabolism—glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)—is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39‐compound library does

  葡萄糖基神经酰胺的代谢和涉及的酶已在药物化学中引起了极大的兴趣，因为源自葡萄糖基神经酰胺的糖脂水平的异常是导致一系列人类疾病（包括溶酶体贮积病，2型糖尿病和神经退行性疾病）的原因。因此，对参与糖基神经酰胺代谢的一种糖加工酶（糖基神经酰胺合酶（GCS），酸性糖基神经酰胺酶（GBA1）或中性糖基神经酰胺酶（GBA2））的选择性调节是一个有吸引力的研究目标。在这项研究中，我们采用了两种已建立的GCS抑制剂，一种基于脱氧野oji霉素，另一种基于神经酰胺类似物，并合并了特征性特征以获得杂化化合物。所得的39个化合物文库不包含新的GCS抑制剂。但是，有效的（200 nm）鉴定出对GBA2几乎没有活性的GBA1抑制剂，因此可以作为选择性GBA1调节剂作为进一步生物医学开发的先导。
• A Short and Efficient Synthesis of 1,5-Dideoxy-1,5-imino-d-galactitol (1-deoxy-d-Galactostatin) and 1,5-Dideoxy-1,5-imino-l-altritol (1-deoxy-l-Altrostatin) from d-Galactose
  作者：Clara Uriel、Francisco Santoyo-González

  DOI：10.1055/s-1999-3158

  日期：1999.5

  A short and efficient route is described for the synthesis of 1-deoxy-d-galactostatin and 1-deoxy-l-altrostatin starting from d-galactose.

  介绍了从d-半乳糖出发合成1-脱氧-d-半乳抑制素和1-脱氧-l-阿朴霉素的简短而高效的路线。
• Iminosugar glycoconjugates
  申请人：Technische Universität Graz

  公开号：EP1903034A1

  公开（公告）日：2008-03-26

  The iminosugar conjugates according to the invention are N-alkylated 1,5-dideoxy-1,5-iminohexitol or 1,5-dideoxy-1,5-iminopentitol derivatives. The iminosugar component can be, for example, D-gluco-, L-ido-, D-galacto-, D-manno-, 2-acetamido-2-deoxy-D-gluco- or xylo-configuration. The N-substituent is a protected L-α-aminoacid derivative, showing L-lysine-like structural features. The linkage between the carbohydrate and the peptide component is not via the usual glycosidic position, but shows structural features of a very stable tertiary amine. Thus the linkage is very stable. These new compounds are synthesised by using catalytic intramolecular reductive amination of dicarbonyl sugars with partially protected amino acids. The process of intramolecular reductive amination itself is carried out using Pearlman's catalyst (Pd(OH)2/C) and H2 at ambient pressure and room temperature. The resulting accessible class of iminosugar conjugate compounds is represented by the general structure shown in Figure 4(c). The alkyl chain length parameter n can be freely chosen from n=0 upwards. Preferably n is between 0 and 10, and more preferably n is 2, 3, or 4. Residue R1 can be chosen from H, OH, or NHAc, with Ac being Acetyl. R2 can be H, OH, or NHAc. R3, R4, R5, R6 can be H or OH. R7 and R8 can be H, CH2OH CH3, COQH, or COOR with R being Alkyl or Aryl. R9 and R10 can be chosen from H, NH2, NHR, with R being a protective group, an amino acid, a peptide, or a protein. R11 can be OH, O-Alkyl, O-Aryl, NH2, N-Alkyl, N-Aryl, amino acid or peptide, connected via an amide bond.

  本发明涉及的亚氨基糖缀合物是N-烷基化的1,5-二脱氧-1,5-亚氨基己糖醇或1,5-二脱氧-1,5-亚氨基戊糖醇衍生物。亚氨基糖部分可以是例如D-葡萄糖、L-艾杜糖、D-半乳糖、D-甘露糖、2-乙酰氨基-2-脱氧-D-葡萄糖或木糖构型。N-取代基是一种保护的L-α-氨基酸衍生物，显示出类似L-赖氨酸的结构特征。糖和肽组分之间的连接不是通过常规的糖苷位置，而是显示出非常稳定的叔胺的结构特征。因此，这种连接非常稳定。这些新化合物是通过使用催化剂催化二羰基糖与部分保护的氨基酸之间的分子内还原胺化合成的。分子内还原胺化过程本身是在常压和室温下使用Pearlman催化剂（Pd(OH)2/C）和氢气进行的。由此得到的一类亚氨基糖缀合物化合物的可及性由图4(c)所示的通用结构表示。烷基链长参数n可以从n=0开始自由选择。优选n在0到10之间，更优选n为2、3或4。残基R1可以从H、OH或NHAc中选择，其中Ac代表乙酰基。R2可以是H、OH或NHAc。R3、R4、R5、R6可以是H或OH。R7和R8可以是H、CH2OH、CH3、COQH或COOR，其中R是烷基或芳基。R9和R10可以从H、NH2、NHR中选择，其中R是一个保护基团、氨基酸、肽或蛋白质。R11可以是OH、O-烷基、O-芳基、NH2、N-烷基、N-芳基、氨基酸或肽，通过酰胺键连接。