Sphingolipids were originally characterized as metabolites that accumulate from the loss of activity of specific lysosomal hydrolases resulting in significant organ specific pathologies. A subclass of sphingolipids, glycosphingolipids, is highly complex with greater than 300 distinct species found in mammalian tissues. Glycosphingolipids comprise a minor fraction of cellular lipid mass but they have emerged as important mediators of cellular function.
We have targeted glycosphingolipid synthesis through the development of small molecule inhibitors of glucosylceramide synthase, first as probes for better understanding the biology of glycolipids and subsequently as a strategy for the treatment of lysosomal storage diseases. A pharmacophore was identified based on the structure of glucosylceramide and a series of inhibitors were developed. D-threo-1-ethylendioxyphenyl-2-octanoylamino-3-pyrrolidino-propanol (eliglustat tartrate), was found to be a highly active and specific inhibitor of the cerebroside synthase. Eliglustat was the basis for phase 2 and 3 clinical trials for Gaucher disease type 1 and subsequently approved by the FDA and EMA as the first stand-alone oral agent for Gaucher disease.
Recent work has focused on the potential use of glucosylceramide synthesis inhibition for indications that extend beyond the treatment of Gaucher disease type 1. These studies address three broad questions. First, can glucosylceramide synthesis inhibition be used for the treatment of other glycosphingolipidoses? Second, will the inhibition of glucosylceramide synthesis be beneficial in diseases in which glycosphingolipids are contributory to the cause or progression of the disease? Third, is glycolipid synthesis inhibition beneficial in the treatment of disorders in which aerobic glycolysis is favored?