Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Abstract

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

Detection of Active Mammalian GH31 α-Glucosidases in Health and Disease Using In-Class, Broad-Spectrum Activity-Based Probes

“…As reference competitive inhibitors, we used deoxynojirimycin derivatives 18 – 22 and maltose 23 ( Figure S1 ). 23 …”

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

“…The enzymes catalyzing the biosynthesis and lysosomal hydrolysis of GlcCer, UGCG, and GBA, respectively, are the subjects of multiple medicinal chemistry studies employing alkylated derivatives of the imino sugar deoxynojirimycin, deoxygalactonojirimycin (23)(24)(25)(26), and related compounds (27)(28)(29). Inhibition of UGCG using alkylated imino sugars is the FIGURE 1.…”

A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals

“…Plant carbohydrate metabolic processes, including starch, cell wall, glycolipid and glycoprotein synthesis and degradation, are essential to seedling establishment and have implications for crop quality, utilisation and pathogen resistance 1 – 3 . Furthermore, detailed understanding of these systems can be applied to develop better processing in value-added sectors, such as malting, brewing and food manufacture.…”

“…Work to increase iminosugar potency and selectivity has focused on human GCS and other human glycoprocessing enzymes. A large collection of N -alkyl substituents, as well as structural and stereochemical analogues of the d - gluco -configured N -Bu-DNJ have been synthesised to analyse how inhibitor structure alters selectivity for GCS over GCase and other glucosidases 1 , 34 – 38 .…”