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The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity?

The treatment of glycosphingolipid storage diseases by synthesis inhibition was first proposed 40 years ago as an alternative approach to enzyme replacement therapy. We have pursued this strategy through the rational design of potent and selective inhibitors of glucosylceramide synthase, the first step in glycosphingolipid synthesis. Eliglustat tartrate was the result of these efforts and is currently the focus of phase 3 trials for type 1 Gaucher disease. Phase 2 studies showed a reduction in splenomegaly and hepatomegaly and improvements of anemia and thrombocytopenia at levels equivalent to or exceeding the historic response to imiglucerase. Structural analogues of eliglustat have also been designed that lack pgp-1 recognition and cross the blood brain barrier. These may have utility for central nervous system- based sphingolipidoses. Because glycosphingolipids are important regulators of receptor tyrosine kinases, glucosylceramide synthase inhibitors may also be beneficial for disorders such as type 2 diabetes mellitus and polycystic kidney disease.