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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ghisaidoobe, Amar Bikker, Pieter de Bruijn, Arjan C. J. Godschalk, Frithjof D. Rogaar, Eva Guijt, Marieke C. Hagens, Peter Halma, Jerre M. Van't Hart, Steven M. Luitjens, Stijn B. Van Rixel, Vincent H. S. Wijzenbroek, Mark Zweegers, Thor Donker-Koopman, Wilma E. Strijland, Anneke Boot, Rolf Van Der Marel, Gijs Overkleeft, Herman S. Aerts, Johannes M. F. G. Van Den Berg, Richard J. B. H. N.
Description	Country affiliation: Netherlands Author Affiliation: Ghisaidoobe A ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Bikker P ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); de Bruijn AC ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Godschalk FD ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Rogaar E ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Guijt MC ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Hagens P ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Halma JM ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Van't Hart SM ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Luitjens SB ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); van Rixel VH ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Wijzenbroek M ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Zweegers T ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Donker-Koopman WE ( Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.); Strijland A ( Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.); Boot R ( Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.); van der Marel G ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Overkleeft HS ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.); Aerts JM ( Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.); van den Berg RJ ( Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.)
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.
File Format	HTM / HTML
e-ISSN	19485875
DOI	10.1021/ml100192b
Journal	ACS Medicinal Chemistry Letters
Issue Number	2
Volume Number	2
Language	English
Publisher	American Chemical Society
Publisher Date	2011-02-10
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Chemistry
Content Type	Text
Resource Type	Article

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