Rapid modifications of N-substitution in iminosugars: Development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease

• Published in: Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.5021-5028
• Main Authors: Cheng, Wei-Chieh, Weng, Chen-Yi, Yun, Wen-Yi, Chang, Shang-Yu, Lin, Yu-Chun, Tsai, Fuu-Jen, Huang, Fu-Yung, Chen, Yun-Ru
• Format: Article
• Language: English
• Subjects: alpha-glucosidase; Binding Sites; carboxylic acids; Cell Line; Chemical chaperone; chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; fibroblasts; Gaucher disease; Gaucher Disease - enzymology; Gaucher Disease - pathology; GCase inhibitor; Glucosylceramidase - antagonists & inhibitors; Glucosylceramidase - metabolism; Glycosidases; Humans; Imino Sugars - chemical synthesis; Imino Sugars - chemistry; Imino Sugars - metabolism; Iminosugar; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.06.054

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.