Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

作者：van den Berg Richard J B H N; Wennekes Tom; Ghisaidoobe Amar; Donker Koopman Wilma E; Strijland Anneke; Boot Rolf G; van der Marel Gij**ert A; Aerts Johannes M F G^*; Overkleeft Herman S

来源：ACS Medicinal Chemistry Letters, 2011, 2(7): 519-522.

DOI：10.1021/ml200050s

• Glucosylceramide synthase
• iminosugar
• Gaucher disease
• ceramide
• deoxynojirimycin

Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.

• 出版日期2011-7