Potent Aminocyclitol Glucocerebrosidase Inhibitors are Subnanomolar Pharmacological Chaperones for Treating Gaucher Disease

Amino-<i>myo</i>-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1<i>R</i>,2<i>S</i>,3<i>R</i>,4<i>S</i>,5<i>S</i>,6<i>R</i>)-5-(nonylamino)-6-(nonyloxy)­cyclohexane-1,2,3,4-tetraol had a <i>K</i>_i of 1 nM using isolated enzyme and an IC₅₀ of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment