Synthesis of N-alkylated noeurostegines and evaluation of their potential as treatment for Gaucher's disease

Rassmussen, T. S., Allman, S., Twigg, G., Butters, T. D. and Jensen, H. H. (2011) Synthesis of N-alkylated noeurostegines and evaluation of their potential as treatment for Gaucher's disease. Bioorganic & Medicinal Chemistry Letters, 21 (5). pp. 1519-1522. ISSN 0960-894X doi: 10.1016/j.bmcl.2010.12.106

Abstract/Summary

The potent and selective inhibitor of β-glucosidases, noeurostegine, was evaluated as an inhibitor of glucocerebrosidase (GCase) to give an IC50 value of 0.4 μM, being 250- and 150-fold better than N-butyl and N-nonyl noeurostegine, respectively. The parent noeurostegine and its N-butyl and N-nonyl alkylated congeners were also tested as pharmacological chaperones against a N370S GCase mutant. Of these, only noeurostegine, was found to increase enzyme activity, which in potency was comparable to that previously reported for isofagomine.