Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors |
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| Authors: | Dr Richard J B H N van den Berg Dr Erwin R van Rijssel Maria Joao Ferraz Judith Houben Anneke Strijland Wilma E Donker‐Koopman Dr Tom Wennekes Dr Kimberly M Bonger Dr Amar B T Ghisaidoobe Dr Sascha Hoogendoorn Prof Dr Gijsbert A van der Marel Dr Jeroen D C Codée Prof Dr Herman S Overkleeft Prof Dr Johannes M F G Aerts |
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| Affiliation: | 1. Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands;2. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;3. Laboratory of Organic Chemistry, Wageningen University, Wageningen, The Netherlands |
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| Abstract: | Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism—glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)—is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39‐compound library does not contain new GCS inhibitors; however, a potent (200 nm ) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator. |
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| Keywords: | acid glucosylceramidase ceramide analogues deoxynojirimycin glucosylceramide synthase neutral glucosylceramidase |
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