title: Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars.
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.
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Amar
authors.initials: A
authors.lastname: Ghisaidoobe
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Bikker
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Arjan C J
authors.initials: AC
authors.lastname: de Bruijn
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Frithjof D
authors.initials: FD
authors.lastname: Godschalk
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Rogaar
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Marieke C
authors.initials: MC
authors.lastname: Guijt
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Hagens
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Jerre M
authors.initials: JM
authors.lastname: Halma
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Van't Hart
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Stijn B
authors.initials: SB
authors.lastname: Luitjens
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Vincent H S
authors.initials: VH
authors.lastname: van Rixel
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Wijzenbroek
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Thor
authors.initials: T
authors.lastname: Zweegers
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Donker-Koopman
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Boot
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: van der Marel
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
keywords: Gaucher; acid glucosylceramidase; deoxynojirimycin; glucosylceramide synthase; type 2 diabetes