title: 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 increase in enzyme activity over a relatively wide dosage range. The data assembled here illustrate how the lipophilic moiety common to many glucocerebrosidase inhibitors might be used to optimize a lead compound's ability to chaperone the protein in cellulo. The flexibility of this synthetic strategy makes it an attractive approach to the rapid optimization of glycosidase inhibitor potency and pharmacokinetic behavior.
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T 1Z1, Canada.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Goddard-Borger
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tropak
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yonekawa
authors.forename: Christina
authors.initials: C
authors.lastname: Tysoe
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahuran
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology; D057075:Enzyme Assays; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000494:pharmacology; D007536:Isomerism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D009154:Mutation; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014993:Xylitol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002241:Carbohydrates; D007097:Imines; D054852:Small Molecule Libraries; D000499:Allylamine; D005962:Glucosylceramidase; D014993:Xylitol