In:
ChemMedChem, Wiley, Vol. 10, No. 12 ( 2015-12), p. 2042-2062
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 n m ) 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201500407
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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