17 results on '"Isofagomine"'
Search Results
2. The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases
- Author
-
James A. Shayman and Scott D. Larsen
- Subjects
lysosome ,glucosylceramide ,pharmacological chaperone ,eliglustat tartrate ,miglustat ,isofagomine ,Biochemistry ,QD415-436 - Abstract
Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review.
- Published
- 2014
- Full Text
- View/download PDF
3. Beta-glucosidase 1 (GBA1) is a second bile acid β-glucosidase in addition to β-glucosidase 2 (GBA2). Study in β-glucosidase deficient mice and humans
- Author
-
Harzer, Klaus, Blech-Hermoni, Yotam, Goldin, Ehud, Felderhoff-Mueser, Ursula, Igney, Claudia, Sidransky, Ellen, and Yildiz, Yildiz
- Subjects
- *
GAUCHER'S disease diagnosis , *BETA-glucosidase , *BILE acids , *GLUCOSYLCERAMIDES , *LITHOCHOLIC acid , *FIBROBLASTS , *LABORATORY mice - Abstract
Abstract: Beta-glucosidase 1 (GBA1; lysosomal glucocerebrosidase) and β-glucosidase 2 (GBA2, non-lysosomal glucocerebrosidase) both have glucosylceramide as a main natural substrate. The enzyme-deficient conditions with glucosylceramide accumulation are Gaucher disease (GBA−/− in humans), modelled by the Gba−/− mouse, and the syndrome with male infertility in the Gba2−/− mouse, respectively. Before the leading role of glucosylceramide was recognised for both deficient conditions, bile acid-3-O-β-glucoside (BG), another natural substrate, was viewed as the main substrate of GBA2. Given that GBA2 hydrolyses both BG and glucosylceramide, it was asked whether vice versa GBA1 hydrolyses both glucosylceramide and BG. Here we show that GBA1 also hydrolyses BG. We compared the residual BG hydrolysing activities in the GBA1−/−, Gba1−/− conditions (where GBA2 is the almost only active β-glucosidase) and those in the Gba2−/− condition (GBA1 active), with wild-type activities, but we used also the GBA1 inhibitor isofagomine. GBA1 and GBA2 activities had characteristic differences between the studied fibroblast, liver and brain samples. Independently, the hydrolysis of BG by pure recombinant GBA1 was shown. The fact that both GBA1 and GBA2 are glucocerebrosidases as well as bile acid β-glucosidases raises the question, why lysosomal accumulation of glucosylceramide in GBA1 deficiency, and extra-lysosomal accumulation in GBA2 deficiency, are not associated with an accumulation of BG in either condition. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
4. Docking and SAR studies of d- and l-isofagomine isomers as human β-glucocerebrosidase inhibitors
- Author
-
Kato, Atsushi, Miyauchi, Saori, Kato, Noriko, Nash, Robert J., Yoshimura, Yuichi, Nakagome, Izumi, Hirono, Shuichi, Takahata, Hiroki, and Adachi, Isao
- Subjects
- *
STRUCTURE-activity relationships , *MOLECULAR chaperones , *GLYCOSIDASE inhibitors , *HYDROGEN bonding , *GAUCHER'S disease treatment , *GLYCOSIDASES - Abstract
Abstract: We report the structure–activity relationship of a series of d-, and l-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, d-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. l-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC50 value of 8.7μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of d-3-epi-isofagomine in the binding site was similar to that of d-isofagomine, while d-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that d-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
5. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of β-glucosidase.
- Author
-
Khanna, Richie, Benjamin, Elfrida R., Pellegrino, Lee, Schilling, Adriane, Rigat, Brigitte A., Soska, Rebecca, Nafar, Hadis, Ranes, Brian E., Feng, Jessie, Lun, Yi, Powe, Allan C., Palling, David J., Wustman, Brandon A., Schiffmann, Raphael, Mahuran, Don J., Lockhart, David J., and Valenzano, Kenneth J.
- Subjects
- *
MOLECULAR chaperones , *GENETIC mutation , *GLUCOSIDASES , *LYSOSOMAL storage diseases , *CELL lines - Abstract
Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid β-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5- and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2- to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease. Structured digital abstract • , , : LAMP1 (uniprotkb: ) and GCase (uniprotkb: ) colocalize ( ) by fluorescence microscopy ( ) [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
6. Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase
- Author
-
Steet, Richard, Chung, Stephen, Lee, Wang-Sik, Pine, Corey W., Do, Hung, and Kornfeld, Stuart
- Subjects
- *
GAUCHER'S disease treatment , *MOLECULAR chaperones , *GLUCOSIDASES , *GLYCOLIPIDS - Abstract
Abstract: Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-β-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 α-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. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
7. Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients.
- Author
-
Hui-Hwa Chang, Asano, Naoki, Ishii, Satoshi, Ichikawa, Yoshitaka, and Jian-Qiang Fan
- Subjects
- *
GAUCHER'S disease , *FIBROBLASTS , *CEREBROSIDE metabolism disorders , *LYSOSOMES , *RETICULO-endothelial system , *ALKALOIDS , *PATIENTS - Abstract
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the deficient activity of glucocerebrosidase. Accumulation of glucosylceramide, primarily in the lysosomes of cells of the reticuloendothelial system, leads to hepatosplenomegaly, anemia and skeletal lesions in type I disease, and neurologic manifestations in types II and III disease. We report herein the identification of hydrophilic active-site-specific chaperones that are capable of increasing glucocerebrosidase activity in the cultured fibroblasts of Gaucher patients. Screening of a variety of natural and synthetic alkaloid compounds showed isofagomine, N-dodecyl deoxynojirimycin, calystegines A3, B1, B2 and C1, and 1,5-dideoxy-1,5-iminoxylitol to be potent inhibitors of glucocerebrosidase. Among them, isofagomine was the most potent inhibitor of glucocerebrosidase in vitro, and the most effective active-site-specific chaperone capable of increasing residual glucocerebrosidase activity in fibroblasts established from Gaucher patients with the most prevalent Gaucher disease-causing mutation (N370S). Intracellular enzyme activity increased approximately two-fold after cells had been incubated with isofagomine, and the increase in glucocerebrosidase activity was both dose-dependent and time-dependent. Western blotting demonstrated that there was a substantial increase in glucocerebrosidase protein in cells after isofagomine treatment. Immunocytochemistry revealed an improvement in the glucocerebrosidase trafficking pattern, which overlaps that of lysosome-associated membrane protein 2 in Gaucher fibroblasts cultivated with isofagomine, suggesting that the transport of mutant glucocerebrosidase is at least partially improved in the presence of isofagomine. The hydrophilic active-site-specific chaperones are less toxic to cultured cells. These results indicate that these hydrophilic small molecules are suitable candidates for further drug development for the treatment of Gaucher disease. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
8. A short and concise synthesis of isofagomine, homoisofagomine, and 5′-deoxyisofagomine
- Author
-
Ouchi, Hidekazu, Mihara, Yukiko, Watanabe, Hitomi, and Takahata, Hiroki
- Published
- 2004
- Full Text
- View/download PDF
9. Synthesis of novel 1-N-iminosugars from chiral nonracemic bicyclic lactams
- Author
-
Xie, Juan, Güveli, Tatyana, Hebbe, Séverine, and Dechoux, Luc
- Subjects
- *
LACTAMS , *HETEROCYCLIC compounds , *IMINO compounds , *CHIRALITY - Abstract
This communication reported the synthesis of novel C-6 substituted isofagomine analogues from easily accessible chiral nonracemic bicyclic lactams. These azasugars have potentially very interesting structure and are difficult to obtain by other methods. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
10. Synthesis and Chemistry of Noeuromycin and Isofagomine Analogues.
- Author
-
Liu, Huizhen, Lillelund, VinniH., Andersch, Jens, Liang, Xifu, and Bols, Mikael
- Subjects
- *
PIPERIDINE , *HETEROCYCLIC compounds , *CHEMISTRY , *CARBOHYDRATES - Abstract
Several N-substituted analogues of noeuromycin((2RS,3S,4R,5R)-2,3,4-trihydroxy-5-hydroxymethylpiperidine) and isofagomine((3R,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidine) were synthesised. The isofagomine analogues(3RS,4RS,5RS)-N-(2-phosphonoethyl)-3,4-dihydroxy-5-hydroxymethyl-piperidine,(3SR,4SR,5RS)-N-(2-phosphonoethyl)-3,4-dihydroxy-5-hydroxy-methylpiperidine, and(3R,4R,5R)-N-(10-chloro-9-anthracenemethyl)-3,4-dihydroxy-5-hydroxy-methylpiperidine were synthesised by direct alkylation of the corresponding azasugar. N-Substituted noeuromycin derivatives could not be made in this straightforward manner, but were made by modification of a synthesis intermediate. By this method(2RS,3S,4R,5R)-N-(4-methoxyphenyl)-2,3,4-trihydroxy-5-hydroxymethylpiperidine and(2RS,3S,4R,5R)-N-nonyl-2,3,4-trihydroxy-5-hydroxymethylpiperidine were synthesised. The stability of noeuromycin was studied and was found to depend on stereochemistry and pH. The L-fuco isomer((2RS,3R,4R,5R)-2,3,4-trihydroxy-5-methylpiperidine) was observed to undergo a particularly facile Amadori rearrangement at neutral pH to the 3-ketopiperidine. A noeuromycin analogue, that could not undergo the Amadori rearrangement, was synthesised. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
11. The synthesis of a carbohydrate-like dihydrooxazine and tetrahydrooxazine as putative inhibitors of glycoside hydrolases: A direct synthesis of isofagomine.
- Author
-
Best, Wayne M, Macdonald, James M, Skelton, Brian W, Stick, Robert V, Tilbrook, D Matthew G, and White, Allan H
- Subjects
- *
CONFORMATIONAL analysis , *GLYCOSIDASE inhibitors , *SWAINSONINE , *PALLADIUM , *CARBON , *HYDROGEN - Abstract
The treatment of benzyl 2,3-O-isopropylidene-β-L-xylopyranoside with N-hydroxyphthalimide under Mitsunobu conditions, followed by protecting-group interchange, gave benzyl 4-O-[(tert-butoxycarbonyl)amino]-2,3- O-isopropylidene-α-D-arabinoside. Mild acid hydrolysis and catalytic hydrogenolysis afforded 4-O-[(tert-butoxycar bonyl)amino]-D-arabinose that, upon heating in water, gave the dihydrooxazine [(4R,5S,6R)-5,6-dihydro-4,5-dihydroxy-6-hydroxymethyl-4H-1,2-oxazine] as a crystalline solid. A single-crystal structure determination of this solid showed it to exist in the [sup 5] H[sub 6] conformation. Reduction of the dihydrooxazine gave the tetrahydrooxazine [(4R,5S,6R)-4,5-dihy droxy-6-hydroxymethyl-3,4,5,6-tetrahydro-2H-1,2-oxazine]. The dihydrooxazine was an effective inhibitor of two β-glucosidases (K[sub i] = 27 and 35 µM). Benzyl 2,3-O-isopropylidene-β-L-xylopyranoside, via the derived imidazylate, was converted into a nitrile that, upon reduction and protecting-group manipulations, gave benzyl 4-C-aminomethyl-4-deoxy-α-D-arabinoside. Treatment of this amine with hydrogen and palladium-on-carbon gave isofagomine.Key words: dihydrooxazine, tetrahydrooxazine, isofagomine, iminosugars, glycosidase inhibitors.Le traitement du 2,3-O-isopropylidène-β-L-xylopyranoside de benzyle par du N-hydroxyphtalimide dans des conditions de Mitsunobu, suivi d'un échange des groupes protecteurs, conduit à la formation du 4-O-[(tert-butoxycarbonyl)amino]-2,3-O-isopropylidène-α-D-arabinoside de benzyle. Soumis à une hydrolyse acide légère et une hydrogénolyse catalytique, celui-ci fournit alors le 4-O-[(tert-butoxycarbonyl)amino]-D-arabinose qui, par chauffage dans l'eau, livre la dihydrooxazine [(4R,5S,6R)-5,6-dihydro-4,5-dihydroxy-6-hydroxyméthyl-4H-1,2-oxazine] sous la forme de solide cristallin. Une détermination de structure sur un cristal unique montre qu'elle existe dans la conformation [sup 5] H[sub 6] . La réduction de la dihydrooxazine fournit la tétrahydrooxazine [(4R,5S,6R)-4,5-dihydroxy-6-hydroxyméthyl-3,4,5,6-tétrahydro-2H-1,2-oxazine]. La dihydrooxazine est un inhibiteur efficace de deux β-gluco sidases (K[sub i] = 27 et 35 µM). Le 2,3-O-isopropylidène-β-L-xylopyranoside de benzyle, par le biais de l'imidazylate qui en dérive, a été transformé en un nitrile qui, après réduction et des manipulations des groupes protecteurs, fournit le 4-C-aminométhyl-4-désoxy-α-D-arabinoside de benzyle. Le traitement de cette amine avec de l'hydrogène et du palladium sur du charbon conduit alors à l'isofagomine.Mots clés : dihydrooxazine, tétrahydrooxazine, isofagomine, iminosucres, inhibiteurs de glycosidases.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
12. The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases
- Author
-
Scott D. Larsen and James A. Shayman
- Subjects
Glycoside Hydrolases ,Glycoside Hydrolase Inhibitors ,QD415-436 ,Biochemistry ,Glycosphingolipids ,eliglustat tartrate ,chemistry.chemical_compound ,Endocrinology ,Lysosome ,glucosylceramide ,medicine ,Animals ,Humans ,chemistry.chemical_classification ,biology ,ATP synthase ,isofagomine ,Thematic Review ,Cell Biology ,Glycosphingolipid ,Small molecule ,pharmacological chaperone ,Lysosomal Storage Diseases ,Pharmacological chaperone ,medicine.anatomical_structure ,Enzyme ,chemistry ,Chaperone (protein) ,Mutation ,biology.protein ,lysosome ,lipids (amino acids, peptides, and proteins) ,miglustat ,Molecular Chaperones ,medicine.drug - Abstract
Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review.
- Published
- 2014
13. Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients
- Author
-
Chang, Hui-Hwa, Asano, Naoki, Ishii, Satoshi, Ichikawa, Yoshitaka, and Fan, Jian-Qiang
- Subjects
drug design ,glucocerebrosidase ,isofagomine ,Gaucher disease ,active-site-specific chaperone - Abstract
application/pdf, Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the deficient activity of glucocerebrosidase. Accumulation of glucosylceramide, primarily in the lysosomes of cells of the reticuloendothelial system, leads to hepatosplenomegaly, anemia and skeletal lesions in type I disease, and neurologic manifestations in types II and III disease. We report herein the identification of hydrophilic active-site-specific chaperones that are capable of increasing glucocerebrosidase activity in the cultured fibroblasts of Gaucher patients. Screening of a variety of natural and synthetic alkaloid compounds showed isofagomine, N-dodecyl deoxynojirimycin, calystegines A(3), B-1, B-2 and C-1, and 1,5-dideoxy-1,5-iminoxylitol to be potent inhibitors of glucocerebrosidase. Among them, isofagomine was the most potent inhibitor of glucocerebrosidase in vitro, and the most effective active-site-specific chaperone capable of increasing residual glucocerebrosidase activity in fibroblasts established from Gaucher patients with the most prevalent Gaucher disease-causing mutation (N370S). Intracellular enzyme activity increased approximately two-fold after cells had been incubated with isofagomine, and the increase in glucocerebrosidase activity was both dose-dependent and time-dependent. Western blotting demonstrated that there was a substantial increase in glucocerebrosidase protein in cells after isofagomine treatment. Immunocytochemistry revealed an improvement in the glucocerebrosidase trafficking pattern, which overlaps that of lysosome-associated membrane protein 2 in Gaucher fibroblasts cultivated with isofagomine, suggesting that the transport of mutant glucocerebrosidase is at least partially improved in the presence of isofagomine. The hydrophilic active-site-specific chaperones are less toxic to cultured cells. These results indicate that these hydrophilic small molecules are suitable candidates for further drug development for the treatment of Gaucher disease.
- Published
- 2006
14. Compartmentation of Lactate Originating from Glycogen and Glucose in Cultured Astrocytes
- Author
-
Sickmann, Helle M., Schousboe, Arne, Fosgerau, Keld, and Waagepetersen, Helle S.
- Published
- 2005
- Full Text
- View/download PDF
15. Pharmacological chaperone therapy for Gaucher disease: A patent review
- Author
-
Juan M. Benito, Carmen Ortiz Mellet, José M. García Fernández, Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, and Junta de Andalucía
- Subjects
Glucocerebrosidase ,Protein Folding ,Pharmacological chaperone therapy ,Iminosugar ,Drug Evaluation, Preclinical ,Gaucher disease ,Pharmacology ,Biology ,Iminosugars ,lysosomal storage disorders ,Patents as Topic ,Miglustat ,Drug Discovery ,medicine ,Humans ,Substrate reduction therapy ,Enzyme Replacement Therapy ,Gaucher Disease ,Nojirimycin ,Glycosidase inhibitors ,Folding diseases ,General Medicine ,Enzyme replacement therapy ,Isofagomine ,Pharmacological chaperone ,Ambroxol ,Chemical chaperones ,Blood-Brain Barrier ,Drug Design ,Immunology ,Chemical chaperone ,medicine.drug ,Imino Pyranoses ,Molecular Chaperones - Abstract
Introduction: Mutations in the gene encoding for acid β-glucosidase (β-glucocerebrosidase, GlcCerase) are seen in Gaucher disease (GD), which give rise to significant protein misfolding effects and result in progressive accumulation of glucosyl ceramide. The main treatment for GD is enzyme replacement therapy (ERT). The iminosugar glycosidase inhibitor N-(n-butyl)-1-deoxynojirimycin (miglustat, Zavesca™) is used in a second treatment modality known as substrate reduction therapy. At the beginning of the 21st century, a third therapeutic paradigm was launched, namely, pharmacological chaperone therapy (PCT). This therapeutic strategy relies on the capability of such inhibitors to promote the correct folding and stabilize mutant forms of lysosomal enzymes, such as GlcCerase, as they pass through the secretory pathway. Areas covered: This review summarizes the different approaches used to implement the concept of PCT for GD. It discusses the relevant research, patents and patent applications filed in the last decade. Expert opinion: While the significance of PCT remains a matter of debate, the great interest gathered regarding it in a relatively few years reflects its broad potential scope, well beyond GD. The fact that pharmacological chaperones can be designed to cross the blood brain barrier (BBB) make them candidates for the treatment of neuronopathic forms of GD that are not responsive to ERT. Combined therapies offer even broader possibilities that deserve to be fully explored. © 2011 Informa UK, Ltd., The authors thank the the Spanish Ministerio de Ciencia e Innovación (contract numbers CTQ2007-61180/PPQ and SAF2010-84015670), the Fundación Ramón Areces, the Junta de Andalucía (Project P08-FQM-03711) and the European Union for sustained financial support in the field covered by this review.
- Published
- 2011
16. Design and synthesis of acetamido tri- and tetra-hydroxyazepanes: potent and selective beta-N-acetylhexosaminidase inhibitors
- Author
-
Amélia P. Rauter, Pierre Vogel, Filipa Marcelo, Matthieu Sollogoub, Hongqing Li, Terry D. Butters, Claudia Bello, Yves Blériot, and Yongmin Zhang
- Subjects
Inhibitor ,Tay-Sachs ,Stereochemistry ,Clinical Biochemistry ,Iminosugar ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Fungal Proteins ,chemistry.chemical_compound ,Azepane ,Bacterial Proteins ,Drug Discovery ,Glycosidase Inhibitors ,Hexosaminidase Inhibitors ,Osteoarthritis ,Acetamides ,Gem-Diamine 1-N-Iminosugars ,Animals ,Hexosaminidase ,Molecular Biology ,Plant Proteins ,chemistry.chemical_classification ,Fungal protein ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Azepines ,biology.organism_classification ,Isofagomine ,7-Membered Iminocyclitols ,beta-N-Acetylhexosaminidases ,Hexosaminidases ,Glycosidase ,Imino Sugars ,carbohydrates (lipids) ,Enzyme ,Molecular Medicine ,Tetra ,Biological Evaluation ,Glucosidase ,Analogs - Abstract
A series of seven-membered iminosugars bearing an acetamido group beta- or gamma- to the endocyclic nitrogen have been synthesized via simple transformations of previously described polysubstituted azepanes. These tetra- and trihydroxylated acetamido azepanes are ring homologues of 2-acetamido-1,2-dideoxy-glyconojirimycins and 2-acetamido-1-N-iminosugars respectively. Screening of these azepanes towards a range of commercially available glycosidases demonstrated their potential as selective and potent hexosaminidase inhibitors with K-i's in the submicromolar range. A correlation between the relative configuration of the azepanes and their ability to inactivate hexosaminidases was also observed for the first time for this class of compounds with one notable exception for the most potent compound. (C) 2009 Elsevier Ltd. All rights reserved.
- Published
- 2009
17. The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases.
- Author
-
Shayman JA and Larsen SD
- Subjects
- Animals, Humans, Glycoside Hydrolase Inhibitors therapeutic use, Glycoside Hydrolases genetics, Glycoside Hydrolases metabolism, Glycosphingolipids genetics, Glycosphingolipids metabolism, Lysosomal Storage Diseases drug therapy, Lysosomal Storage Diseases genetics, Lysosomal Storage Diseases metabolism, Lysosomal Storage Diseases pathology, Molecular Chaperones therapeutic use, Mutation
- Abstract
Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.