Design of CNS-Permeable Agents for the Treatment of Lipid Storage Diseases

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DESCRIPTION (provided by applicant): Greater than seventy-five distinct lysosomal proteins have been characterized. Genetic mutations of forty-two of these proteins are associated with lysosomal storage diseases. Of these diseases, fourteen are the result of impaired catabolism of sphingolipids and seven of these are due to impaired degradation of glycosphingolipids. These disorders include type I Gaucher disease, Fabry disease, and various central nervous system based diseases. The traditional approach to the treatment of glycosphingolipidoses has been to use enzyme replacement therapy in the form of mannose terminated glycosidases. This strategy, although successful for the treatment of the peripheral manifestations of Fabry and Gaucher disease, is ineffective for CNS based disorders such as Tay-Sachs and Sandhoff disease. Other forms of enzyme replacement, including gene therapy and bone marrow transplantation have been disappointing to date. An alternative strategy has been the inhibition of glycosphingolipid biosynthesis by the use of small molecule inhibitors of glycosphingolipid transferases, most notably glucosylceramide synthase. The PDMP based glucosylceramide analogues represent the paradigm class of glucosylceramide synthase inhibitors. These compounds, discovered and characterized by the Shayman and Radin labs at the University of Michigan, have been widely used by many groups to probe the functions of glycolipids. One PDMP homologue, D-threo-ethylendioxyphenyl-2- octanoylamino-3-pyrrolidino-propanol, is currently in phase II trials for type I Gaucher disease. The PDMP homologues characterized to date, however, have demonstrated poor penetration of the CNS, limiting their potential utility to peripheral tissues. It is hypothesized that the existing PDMP class of potent glucosylceramide synthase inhibitors can be structurally modified to achieve penetration into the CNS without sacrificing key elements of the pharmacaphore. It is further hypothesized that the development of potent small molecule inhibitors of glucosylceramide synthase with efficient CNS permeability will significantly expand the scope of treatable glycosphingolipidoses. Toward these objectives, selected properties of the PDMP template (e.g. molecular weight, polar surface area and number of rotatable bonds) will be modified to more closely approximate those of CNS drugs, using computational models to guide the design. New compounds will be tested in both cell-free and whole cell assays for potency at inhibiting glycosphingolipid synthesis. Evaluations of passive cellular permeability, P-gp mediated efflux and plasma protein binding will be used to predict efficient CNS penetration and to prioritize compounds for in vivo testing. PUBLIC HEALTH RELEVANCE: Current therapy for rare but severely debilitating heritable lipid storage diseases is limited to peripheral tissues, leaving patients with CNS-based lipidoses, including Tay-Sachs, Fabry and Gaucher Types II and III, without effective treatment. Substrate reduction therapy via inhibition of glycosphingolipid biosynthesis holds promise for the treatment of CNS-based lipidoses if agents can be developed that efficiently penetrate the CNS. This proposal will evaluate the feasibility of modifying an established class of small molecule inhibitors of glucosylceramide synthase to achieve potency, specificity and blood brain barrier permeability.