Iminosugars as a new class of cholinesterase inhibitors.

To further extend the scope of iminosugar biological activity, a systematic structure-activity relationship investigation has been performed by synthesizing and evaluating as cholinesterase inhibitors a library of twenty-three iminoalditols with different substitutions and stereochemistry patterns. These compounds have been evaluated in vitro for the inhibition of cholinesterases (different sources of acetylcholinesterase and butyrylcholinesterase). Some compounds have IC50 values in the micromolar range and display significant inhibition selectivity for butyrylcholinesterase over acetylcholinesterase.

Iminosugar-based galactoside mimics as inhibitors of galactocerebrosidase: SAR studies and comparison with other lysosomal galactosidases.

Several families of iminosugar-based galactoside mimics were designed, synthesized, and evaluated as galactocerebrosidase (GALC) inhibitors. They were also tested as inhibitors of lysosomal β- and α-galactosidases in order to find new potent and selective pharmacological chaperones for treatment of the lysosomal storage disorder, Krabbe disease. Whereas 1-C-alkyl imino-L-arabinitols are totally inactive toward the three enzymes, 1-C-alkyl imino-D-galactitols were found to be active only toward α-galactosidase A.

Second-generation iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease.

A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as β-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (α-C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2-shift of the alkyl chain from C1 to O2 was found to maintain high inhibitory potency toward GCase as well as chaperone activity at sub-inhibitory concentration (10 nM).