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

Tina S Rasmussen; Sarah Allman; Gabriele Twigg; Terry D Butters; Henrik H Jensen

doi:10.1016/j.bmcl.2010.12.106

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

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1519-22. doi: 10.1016/j.bmcl.2010.12.106. Epub 2011 Jan 8.

Authors

Tina S Rasmussen¹, Sarah Allman, Gabriele Twigg, Terry D Butters, Henrik H Jensen

Affiliation

¹ Department of Chemistry, Aarhus University, Aarhus C, Denmark.

PMID: 21292481
DOI: 10.1016/j.bmcl.2010.12.106

Abstract

The potent and selective inhibitor of β-glucosidases, noeurostegine, was evaluated as an inhibitor of glucocerebrosidase (GCase) to give an IC(50) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Assays
Gaucher Disease / drug therapy*
Glucosylceramidase / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Nortropanes / chemical synthesis*
Nortropanes / chemistry
Nortropanes / therapeutic use

Substances

Nortropanes
noeurostegine
Glucosylceramidase