Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors

ACS Med Chem Lett. 2011 Apr 7;2(7):519-22. doi: 10.1021/ml200050s.

Richard J B H N van den Berg ¹, Tom Wennekes ¹, Amar Ghisaidoobe ¹, Wilma E Donker-Koopman ², Anneke Strijland ², Rolf G Boot ², Gijsbert A van der Marel ¹, Johannes M F G Aerts ², Herman S Overkleeft ¹

Affiliations

1 Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
2 Department of Medical Biochemistry, Academic Medical Center , Amsterdam, The Netherlands.

PMID: 24900342 DOI: 10.1021/ml200050s

Abstract

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.

Keywords

Gaucher disease; Glucosylceramide synthase; ceramide; deoxynojirimycin; iminosugar.

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