Synthesis and Evaluation of Lipophilic Aza‐C‐glycosides as Inhibitors of Glucosylceramide Metabolism

The structure–activity relationship of lipophilic aza‐C‐glycosides as inhibitors of the three enzymes of glucosylceramide metabolism is investigated. A library of β‐aza‐C‐glycosides was synthesized with variations in N‐alkylation and the linker length/type to the lipophilic moiety. A cross‐metathesis reaction was used to prepare a second library of α‐aza‐C‐glycosides with D‐gluco, L‐ido and D‐xylo iminosugar cores possessing analogous linker variations. Evaluation of both libraries did not reveal a potent or selective inhibitor of glucosylceramide synthase. However, β‐aza‐C‐glycoside 43 was found to be a selective inhibitor of β‐glucosidase 2. The α‐aza‐C‐glycosides – especially with a D‐xylo core (e.g. 80) – proved to be very potent and selective inhibitors of glucocerebrosidase.