(2S,3R,4S,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2S,3R,4S,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol
• 化学式: C₆H₁₄N₂O₃
• 分子量: 162.189
• InChiKey: NJOZFAFEQVQFJI-KCDKBNATSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.0
• 重原子数：
  11.0
• 可旋转键数：
  2.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  98.74
• 氢给体数：
  5.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  3,3-二甲基-1-丁酸 、 (2S,3R,4S,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二甲基亚砜 为溶剂， 生成 N-[[(2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]methyl]-3,3-dimethylbutanamide
  参考文献：
  名称：

  Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease

  摘要：

  The rapid discovery of a pharmacological chaperone toward human alpha-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 x 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue alpha-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other alpha-Gal A mutants in COS7 cells. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.10.004
• 作为产物：
  描述：

  (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyrrole 1-oxide 在 盐酸 、 氢气 、 palladium(II) hydroxide 、 甲基磺酰氯 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 47.33h， 生成 (2S,3R,4S,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol
  参考文献：
  名称：

  [EN] TREATMENT OF FABRY DISEASE
  [FR] TRAITEMENT DE LA MALADIE DE FABRY

  摘要：

  本文揭示了聚羟基吡咯烷的新用途，用于制造治疗法布里病（FD）的药物。因此，本公开提供了一种治疗患有或疑似患有FD的受试者的方法。该方法包括步骤，向受试者施用化合物I式，其盐、酯或溶剂化物的治疗有效量，其中：R1是H，或C1-3胺，可选地取代为-COR2；R2是烷基或烯烃，可选地取代为环烷基或苯基，其至少有一个取代基选自卤素，烷基，卤代烷基和烷氧基的群体；以缓解、减轻和/或预防与FD相关的症状。根据本公开的优选实施例，化合物I式是人类溶酶体α-半乳糖苷酶A（α-Gal A）的突变体的伴侣蛋白。

  公开号：

  WO2017222881A1

文献信息

• From Natural Product‐Inspired Pyrrolidine Scaffolds to the Development of New Human Golgi α‐Mannosidase II Inhibitors
  作者：Ting‐Jen R. Cheng、Ting‐Hao Chan、En‐Lun Tsou、Shang‐Yu Chang、Wen‐Yi Yun、Pei‐Jung Yang、Ying‐Ta Wu、Wei‐Chieh Cheng

  DOI：10.1002/asia.201300680

  日期：2013.11

  of sixteen natural product‐inspired polyhydroylated pyrrolidine‐based isomeric scaffolds is described. Each scaffold possesses four stereogenic centers and one exo‐aminomethyl moiety, which allows for rapid substituent diversity. To exemplify biological applications, these new privileged scaffolds were used to discover new human Golgi α‐mannosidase II inhibitors. The most potent inhibitor shows competitive

  一点启发：本文描述了系统地制备16种以自然产物为灵感的多氢基吡咯烷基异构支架的方法。每个支架都具有四个立体定位中心和一个外氨基氨基甲基部分，可实现快速的取代基多样性。为了举例说明生物学应用，这些新的特权支架被用于发现新的人类高尔基α-甘露糖苷酶II抑制剂。最有效的抑制剂表现出竞争行为，K i值为24 nM。
• [EN] TREATMENT OF FABRY DISEASE<br/>[FR] TRAITEMENT DE LA MALADIE DE FABRY
  申请人：ACADEMIA SINICA

  公开号：WO2017222881A1

  公开（公告）日：2017-12-28

  Disclosed herein are novel uses of a polyhydroxylated pyrrolidine for the manufacture of a medicament for treating Fabry disease (FD). Accordingly, the present disclosure provides a method of treating a subject having or suspected of having FD. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), a salt, an ester or a solvate thereof, wherein: R1 is H, or C1-3 amine optionally substituted with -COR2; R2 is alkyl or alkene optionally substituted with cycloalkyl or phenyl having at least one substituent selected from the group consisting of, halo, alkyl, haloalkyl, and alkoxyl; so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the FD. According to preferred embodiments of the present disclosure, the compound of formula (I) is a chaperon of a mutated human lysosomal α-galactosidase A (α-Gal A).

  本文揭示了聚羟基吡咯烷的新用途，用于制造治疗法布里病（FD）的药物。因此，本公开提供了一种治疗患有或疑似患有FD的受试者的方法。该方法包括步骤，向受试者施用化合物I式，其盐、酯或溶剂化物的治疗有效量，其中：R1是H，或C1-3胺，可选地取代为-COR2；R2是烷基或烯烃，可选地取代为环烷基或苯基，其至少有一个取代基选自卤素，烷基，卤代烷基和烷氧基的群体；以缓解、减轻和/或预防与FD相关的症状。根据本公开的优选实施例，化合物I式是人类溶酶体α-半乳糖苷酶A（α-Gal A）的突变体的伴侣蛋白。
• Treatment of Fabry disease
  申请人：Academia Sinica

  公开号：US10995067B2

  公开（公告）日：2021-05-04

  Disclosed herein are novel uses of a polyhydroxylated pyrrolidine for the manufacture of a medicament for treating Fabry disease (FD). Accordingly, the present disclosure provides a method of treating a subject having or suspected of having FD. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), a salt, an ester or a solvate thereof, wherein: R1 is H, or C1-3 amine optionally substituted with —COR2; R2 is alkyl or alkene optionally substituted with cycloalkyl or phenyl having at least one substituent selected from the group consisting of, halo, alkyl, haloalkyl, and alkoxyl; so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the FD. According to preferred embodiments of the present disclosure, the compound of formula (I) is a chaperon of a mutated human lysosomal α-galactosidase A (α-Gal A).

  本文公开了一种聚羟基吡咯烷的新用途，用于制造治疗法布里病（FD）的药物。因此，本公开提供了一种治疗法布里病或疑似法布里病受试者的方法。该方法包括以下步骤：向受试者施用治疗有效量的式(I)化合物、其盐、酯或溶液，其中：R1是H，或任选被-COR2取代的C1-3胺；R2是烷基或烯基，任选被环烷基或苯基取代，环烷基或苯基具有至少一个选自由卤代、烷基、卤代烷基和烷氧基组成的组的取代基；从而改善、减轻和/或预防与FD相关的症状。根据本公开的优选实施方案，式（I）化合物是突变的人溶酶体 α-半乳糖苷酶 A（α-Gal A）的合子。
• Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency
  作者：Wei-Chieh Cheng、Jen-Hon Wang、Huang-Yi Li、Sheng-Jhih Lu、Jia-Ming Hu、Wen-Yi Yun、Cheng-Hsin Chiu、Wen-Bin Yang、Yin-Hsiu Chien、Wuh-Liang Hwu

  DOI：10.1016/j.ejmech.2016.07.025

  日期：2016.11

  A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereo-isomers has been prepared and evaluated for inhibitory activity against alpha-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue alpha-Gal A activity in the lymphoblast of the N215S Fabry patient derived cell line, without impairment of cellular 0-galactosidase activity. When 3-epimer ADMDP was administered with rh-alpha-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-alpha-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease. (C) 2016 Elsevier Masson SAS. All rights reserved.
• TREATMENT OF FABRY DISEASE
  申请人：Academia Sinica

  公开号：US20190225579A1

  公开（公告）日：2019-07-25

  Disclosed herein are novel uses of a polyhydroxylated pyrrolidine for the manufacture of a medicament for treating Fabry disease (FD). Accordingly, the present disclosure provides a method of treating a subject having or suspected of having FD. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), a salt, an ester or a solvate thereof, wherein: R 1 is H, or C 1-3 amine optionally substituted with —COR 2 ; R 2 is alkyl or alkene optionally substituted with cycloalkyl or phenyl having at least one substituent selected from the group consisting of, halo, alkyl, haloalkyl, and alkoxyl; so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the FD. According to preferred embodiments of the present disclosure, the compound of formula (I) is a chaperon of a mutated human lysosomal α-galactosidase A (α-Gal A).