Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its subst...

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Published in:ACS medicinal chemistry letters 2011-07, Vol.2 (7), p.519-522
Main Authors: van den Berg, Richard J. B. H. N, Wennekes, Tom, Ghisaidoobe, Amar, Donker-Koopman, Wilma E, Strijland, Anneke, Boot, Rolf G, van der Marel, Gijsbert A, Aerts, Johannes M. F. G, Overkleeft, Herman S
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Language:English
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Summary:Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml200050s