Identification of Potent and Selective Glucosylceramide SynthaseInhibitorsfromaLibraryof N-AlkylatedIminosugars

摘要

Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promis- ing target for combating type 2 diabetes. Iminosugars are useful leads for the devel- opment 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 glucosylcer- amidase (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 poten- tial chemical chaperones. The physiological importance of GBA2 in glucosylcer- amide processing in relation to disease states is less clear, and here, selective inhib- itors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated -ido-configured L iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.