Agents for the Treatment of Glycosphingolipid Storage Disorders

Authors: Abe A.; Wild S.R.; Lee L.; Shayman J.A.

Source: Current Drug Metabolism, Volume 2, Number 3, September 2001 , pp. 331-338(8)

Publisher: Bentham Science Publishers

Abstract:

We have developed a series of inhibitors of glucosylceramide synthase that are Structurally based on the parent compound D-threo-1-phenyl-2-decanoylamino-3- morpholino-1-propanol (PDMP). These inhibitors provide useful tools for manipulating glycosphingolipid levels in cells and for elucidating questions associated with sphingolipid signaling. Recently, two highly active glucosylceramide synthase inhibitors, D-threo-3, 4 -ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol and D-threo-4-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, were designed, synthesized, and studied. These inhibitors markedly reduced glycosphingolipid levels in MDCK cells without any accumulation of intracellular ceramide and associated growth inhibition. Subsequently, each inhibitor was evaluated for its ability to lower glycolipid levels in virally transformed lymphoblasts from a patient with a-galactosidase A deficiency. Both compounds significantly reduced neutral glycosphingolipid levels in the lymphoblasts without any morphological changes and growth inhibition. Furthermore, the inhibitors were applied to a mouse knockout model of Fabry disease. Inhibitor treatment blocked accumulation of globotriaosylceramide (Gb3) in the kidney, liver and heart of mice. In contrast to another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, this treatment was not associated with any significant change in body weight or organ weight and without immunodepletion. These results suggest that these newest PDMP homologues are promising as therapeutic agents for the treatment of glycosphingolipid storage disorders.

Keywords: Glycosphingolipid Storage Disorders; MDCK cells; Glucosylceramide (GlcCer); Glycosphingolipidoses; PDMP; D-threo-1-Phenyl-2-Palmitoylamino-3-Py-rrolidino-

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200013338414

Publication date: 2001-09-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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• In this Subject: Anatomy & Physiology ,  Pharmacology
• By this author: Abe A. ;  Wild S.R. ;  Lee L. ;  Shayman J.A.

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