Previous work has led to the identification of inhibitors of glucosylceramide synthase, the
enzyme catalyzing the first glycosylation step in the synthesis of glucosylceramide-based
glycosphingolipids. These inhibitors have two identified sites of action: the inhibition of
glucosylceramide synthase, resulting in the depletion of cellular glycosphingolipids, and the
inhibition of 1-O-acylceramide synthase, resulting in the elevation of cell ceramide levels. A
new series of glucosylceramide synthase inhibitors based on substitutions in the phenyl ring …