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

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† Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC−CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
‡ Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom
*Phone: 34-934-006-108. Fax: +34-932045904. E-mail: [email protected]
Cite this: J. Med. Chem. 2012, 55, 9, 4479–4488
Publication Date (Web):April 19, 2012
https://doi.org/10.1021/jm300342q
Copyright © 2012 American Chemical Society
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    Abstract

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    Amino-myo-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, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a Ki 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.

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    General experimental protocols and compound characterization data for all new compounds, as well as experimental procedure for glycosidase inhibition assays, GCS inhibition in cell homogenates, cytotoxicity, GCase and GBA2 inhibition in mouse tissue homogenates, stabilization ratios after thermal denaturation of recombinant GCase (Imiglucerase), and the effects of compounds on L444P or N370S GCase activity in GD lymphoblasts. This material is available free of charge via the Internet at http://pubs.acs.org.

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