Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars

ACS Med Chem Lett. 2010 Dec 2;2(2):119-23. doi: 10.1021/ml100192b.

Amar Ghisaidoobe ¹, Pieter Bikker ¹, Arjan C J de Bruijn ¹, Frithjof D Godschalk ¹, Eva Rogaar ¹, Marieke C Guijt ¹, Peter Hagens ¹, Jerre M Halma ¹, Steven M Van't Hart ¹, Stijn B Luitjens ¹, Vincent H S van Rixel ¹, Mark Wijzenbroek ¹, Thor Zweegers ¹, Wilma E Donker-Koopman ², Anneke Strijland ², Rolf Boot ², Gijs van der Marel ¹, Herman S Overkleeft ¹, Johannes M F G Aerts ², Richard J B H N van den Berg 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: 24900289 DOI: 10.1021/ml100192b

Abstract

Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward Other glyco-processing Enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two Enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

Keywords

Gaucher; acid glucosylceramidase; deoxynojirimycin; glucosylceramide synthase; type 2 diabetes.

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