Rapid Assembly of a Library of Lipophilic Iminosugars via the Thiol–Ene Reaction Yields Promising Pharmacological Chaperones for the Treatment of Gaucher Disease

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

Rapid Assembly of a Library of Lipophilic Iminosugars via the Thiol–Ene Reaction Yields Promising Pharmacological Chaperones for the Treatment of Gaucher Disease

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

Synthesis of 1,5-Dideoxy-1,5-iminoribitol <i>C</i>‑Glycosides through a Nitrone–Olefin Cycloaddition Domino Strategy: Identification of Pharmacological Chaperones of Mutant Human Lysosomal β‑Galactosidase

We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar <i>C</i>-glycosides <b>7a</b>–<b>e</b> and <b>8</b>. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines <b>10a</b>–<b>e</b> in a “one-pot” protocol. The iminoribitol <i>C</i>-glycosides <b>7a</b>–<b>e</b> and <b>8</b> were found to be modest β-galactosidase (bGal) inhibitors. However, compounds <b>7c</b> and <b>7e</b> showed “pharmacological chaperone” activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2–6-fold