Iminosugar‐Based Galactoside Mimics as Inhibitors of Galactocerebrosidase: SAR Studies and Comparison with Other Lysosomal Galactosidases
Résumé
Abstract 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. Finally, 1‐ N ‐iminosugars provided the best results, as 4‐epi‐isofagomine was found to be a good inhibitor of both lysosomal β‐galactosidase and GALC. Further elaboration of this structure is required to achieve selectivity between these two galactosidases.