Abstract |
The rapid discovery of β- 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 71nM. 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 α- 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 α- glucosidase activity.
|
Authors | Wei-Chieh Cheng, Chen-Yi Weng, Wen-Yi Yun, Shang-Yu Chang, Yu-Chun Lin, Fuu-Jen Tsai, Fu-Yung Huang, Yun-Ru Chen |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 21
Issue 17
Pg. 5021-8
(Sep 01 2013)
ISSN: 1464-3391 [Electronic] England |
PMID | 23880081
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2013 Elsevier Ltd. All rights reserved. |
Chemical References |
- Enzyme Inhibitors
- Imino Sugars
- Glucosylceramidase
|
Topics |
- Binding Sites
- Cell Line
- Enzyme Inhibitors
(chemical synthesis, chemistry, metabolism)
- Gaucher Disease
(enzymology, pathology)
- Glucosylceramidase
(antagonists & inhibitors, metabolism)
- Humans
- Imino Sugars
(chemical synthesis, chemistry, metabolism)
- Molecular Docking Simulation
- Protein Binding
- Protein Structure, Tertiary
|