piperidines and miglustat

Metabolic storage disorders are caused by mutations in genes that result in insufficient activity of enzymes required for the catabolism of substances that arise from the turnover of senescent cells in the body. Among the most prevalent of these conditions are Gaucher disease and Fabry disease, which are caused by reduced activity of the housekeeping enzymes glucocerebrosidase and alpha-galactosidase A, respectively. Enzyme replacement therapy is extraordinarily effective for patients with Gaucher disease. It is under examination in patients with Fabry disease, and improvement of various clinical aspects in these patients has been documented. The blood-brain barrier prevents systemically administered enzymes from reaching the central nervous system. This limitation is a major impediment for the treatment of patients with enzyme deficiency disorders in whom the brain is involved. Alternatives to enzyme replacement therapy that have been initiated to treat systemic manifestations and brain involvement in patients with metabolic disorders include substrate reduction therapy, active site-specific chaperone therapy, and gene therapy. The present status and anticipated advances in the application of these therapeutic approaches are examined here.

Topics: 1-Deoxynojirimycin; Bone Marrow Transplantation; Enzyme Inhibitors; Fabry Disease; Gangliosidosis, GM1; Gaucher Disease; Genetic Therapy; Humans; Imino Sugars; Piperidines

The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any.. Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC.. The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine.. The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.

Topics: 1-Deoxynojirimycin; Adolescent; Adult; Animals; Antiviral Agents; Biological Availability; Butyrates; Dogs; Esterases; Female; HIV; HIV Seropositivity; Humans; Hydrolysis; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Liver; Macaca fascicularis; Male; Piperidines; Prodrugs; Rats; Species Specificity; Subcellular Fractions

Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-beta-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER alpha-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.

Topics: 1-Deoxynojirimycin; alpha-Glucosidases; Cell Proliferation; Cells, Cultured; Disaccharidases; Gaucher Disease; Glucosylceramidase; Glucosyltransferases; Glycoside Hydrolases; Humans; Imino Pyranoses; Lysosomes; Mutation; Oligosaccharides; Piperidines

Conjugate addition of n-butyl amine to d-glucose derived alpha,beta-unsaturated ester 4 afforded beta-amino esters 5a,b that on reduction of ester group, 1,2-acetonide deprotection, and reductive amination led to the formation of corresponding N-butyl 1-deoxy-D-gluco-homonojirimycin 2c and N-butyl 1-deoxy-L-ido-homonojirimycin 2d which were found to be selective beta-glucosidase inhibitors with an IC(50) value in millimolar range.

Topics: 1-Deoxynojirimycin; Amination; Enzyme Inhibitors; Glycoside Hydrolases; Imino Pyranoses; Inhibitory Concentration 50; Models, Chemical; Piperidines