Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors.

Autor:	van den Berg RJ; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., van Rijssel ER; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Ferraz MJ; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Houben J; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Strijland A; Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands., Donker-Koopman WE; Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands., Wennekes T; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.; Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB, Wageningen, The Netherlands., Bonger KM; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Ghisaidoobe AB; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Hoogendoorn S; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., van der Marel GA; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Codée JD; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands., Overkleeft HS; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands. h.s.overkleeft@chem.leidenuniv.nl., Aerts JM; Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands. j.m.aerts@amc.uva.nl.; Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.m.aerts@amc.uva.nl.
Jazyk:	angličtina
Zdroj:	ChemMedChem [ChemMedChem] 2015 Dec; Vol. 10 (12), pp. 2042-62. Date of Electronic Publication: 2015 Oct 23.
DOI:	10.1002/cmdc.201500407
Abstrakt:	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. (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze:	MEDLINE
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