Rapid assembly of a library of lipophilic iminosugars via the thiol-ene reaction yields promising pharmacological chaperones for the treatment of Gaucher disease.

ABSTRACT: A highly divergent route to lipophilic iminosugars that utilizes the thiol-ene reaction was developed to enable the rapid synthesis of a collection of 16 dideoxyiminoxylitols bearing various different lipophilic substituents. Enzyme kinetic analyses revealed that a number of these products are potent, low-nanomolar inhibitors of human glucocerebrosidase that stabilize the enzyme to thermal denaturation by up to 20 K. Cell based assays conducted on Gaucher disease patient derived fibroblasts demonstrated that administration of the compounds can increase lysosomal glucocerebrosidase activity levels by therapeutically relevant amounts, as much as 3.2-fold in cells homozygous for the p.N370S mutation and 1.4-fold in cells homozygous for the p.L444P mutation. Several compounds elicited this inc

SUBMITTER: Goddard-Borger ED 

PROVIDER: S-EPMC3380069 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature