Rapid modifications of N-substitution in iminosugars: Development of new ¦Â-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease
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- 作者：Wei-Chieh Cheng ; Chen-Yi Weng ; Wen-Yi Yun ; Shang-Yu Chang ; Yu-Chun Lin ; Fuu-Jen Tsai ; Fu-Yung Huang ; Yun-Ru Chen
- 关键词：GCase inhibitor ; Chemical chaperone ; Gaucher disease ; Iminosugar ; Glycosidases
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 September, 2013
- 年：2013
- 卷：21
- 期：17
- 页码：5021-5028
- 全文大小：1512 K
文摘
The rapid discovery of ¦Â-glucocerebrosidase (GCase) inhibitors and pharmacological chaperones for Gaucher disease is described. The N-aminobutyl DNJ-based iminosugar was synthesized and conjugating with a variety of carboxylic acids to generate a N-diversely substituted iminosugar-based library. Several members of this library were found to be nanomolar-range inhibitors of GCase; the inhibition constant Ki of the most potent was found to be 71 nM. Although these new molecules showed reasonable chaperoning activity (1.5- to 1.9-fold) in the N370S fibroblast of Gaucher patient-derived cell line, this was accompanies by a concomitant decrease in the cellular ¦Á-glucosidase activity, which might limit their further therapeutic potential. Next, newly developed N-substituents were assembled with pyrrolidine-based scaffolds to generate new molecules for further evaluation. The new 2,5-dideoxy-2,5-imino-d-mannitol (DMDP)-based iminosugar 22 was found to exhibit a satisfactory chaperoning activity to enhance GCase activity by 2.2-fold in Gaucher N370S cell line, without impairment of cellular ¦Á-glucosidase activity.