isofagomine and Gaucher-Disease

isofagomine has been researched along with Gaucher-Disease* in 8 studies

Other Studies

8 other study(ies) available for isofagomine and Gaucher-Disease

ArticleYear
trans, trans-2-C-Aryl-3,4-dihydroxypyrrolidines as potent and selective β-glucosidase inhibitors: Pharmacological chaperones for Gaucher disease.
    European journal of medicinal chemistry, 2022, Aug-05, Volume: 238

    Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives (trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines), designed as β-glucosidase inhibitors by molecular docking calculations, have been synthesized in 2 steps from l- and d-tartaric acid derived enantiomeric cyclic nitrones 29L and 29D, respectively. Both series of C-4 hydroxymethyl depleted DAB and LAB derivatives 28Da-e and 28La-e, which are structurally trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines, were potent and selective human lysosome acid β-glucosidase (GCase) inhibitors, of which 28Dd and 28Ld with C-4 biphenyls showed the highest potency relative to other compounds of the same series. The work provided a series of pyrrolidine-type potent and selective GCase inhibitors with minimal hydroxyl substitutions and synthetic procedures. Structure-activity relationship study revealed not only the rationality of hydrophobic and aromatic properties of the binding sites in GCase, but also the great potential of pyrrolidine family in development of new GCase inhibitors with minimized undesirable side effects. The results indicate a strategy for the development of drugs for the treatment of related diseases targeting acid β-glucosidase, such as Gaucher disease and Parkinson's disease.

    Topics: beta-Glucosidase; Enzyme Inhibitors; Gaucher Disease; Glucosylceramidase; Humans; Molecular Docking Simulation; Pyrrolidines

2022
Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.
    Journal of medicinal chemistry, 2019, 02-14, Volume: 62, Issue:3

    Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene ( GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies.

    Topics: Dopaminergic Neurons; Enzyme Activators; Enzyme Inhibitors; Gaucher Disease; Glucosylceramidase; Humans; Methylation; Parkinson Disease; Quinazolines; Structure-Activity Relationship

2019
Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators.
    Journal of medicinal chemistry, 2016, Sep-22, Volume: 59, Issue:18

    Gaucher's disease is a common genetic disease caused by mutations in the β-glucocerebrosidase (GBA1) gene that have been also linked to increased risk of Parkinson's disease and Lewy body dementia. Stabilization of misfolded mutant β-glucocerebrosidase (GCase) represents an important therapeutic strategy in synucleinopathies. Here we report a novel class of GCase quinazoline inhibitors, obtained in a high throughput screening, with moderate potency against wild-type GCase. Rational design and a SAR study of this class of compounds led to a new series of quinazoline derivatives with single-digit nanomolar potency. These compounds were shown to selectively stabilize GCase when compared to other lysosomal enzymes and to increase N370S mutant GCase protein concentration and activity in cell assays. To the best of our knowledge, these molecules are the most potent noniminosugar GCase modulators to date that may prove useful for future mechanistic studies and therapeutic approaches in Gaucher's and Parkinson's diseases.

    Topics: Cell Line; Drug Design; Enzyme Stability; Gaucher Disease; Glucosylceramidase; Humans; Parkinson Disease; Quinazolines

2016
Docking and SAR studies of calystegines: binding orientation and influence on pharmacological chaperone effects for Gaucher's disease.
    Bioorganic & medicinal chemistry, 2014, Apr-15, Volume: 22, Issue:8

    We report on the identification of the required configuration and binding orientation of nor-tropane alkaloid calystegines against β-glucocerebrosidase. Calystegine B2 is a potent competitive inhibitor of human lysosomal β-glucocerebrosidase with Ki value of 3.3 μM. A molecular docking study revealed that calystegine B2 had a favorable van der Waals interactions (Phe128, Trp179, and Phe246) and the hydrogen bonding (Glu235, Glu340, Asp127, Trp179, Asn234, Trp381 and Asn396) was similar to that of isofagomine. All calystegine isomers bound into the same active site as calystegine B2 and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. Calystegine A3 bound to β-glucocerebrosidase with the same orientations as calystegine B2 (Type 1), while calystegine B3 and B4 had different binding orientations (Type 2). It is noteworthy that Type 1 orientated calystegines B2 and A3 effectively stabilized β-glucocerebrosidase, and consequently increased intracellular β-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines B3 and B4 could not keep the enzyme activity. These results clearly indicate that the binding orientations of calystegines are changed by the configuration of the hydroxyl groups on the nor-tropane ring and the suitable binding orientation is a requirement for achieving a strong affinity to β-glucocerebrosidase.

    Topics: Binding Sites; Catalytic Domain; Cell Line; Gaucher Disease; Glucosylceramidase; Humans; Hydrogen Bonding; Imino Pyranoses; Isomerism; Molecular Docking Simulation; Nortropanes; Solanaceous Alkaloids; Static Electricity; Structure-Activity Relationship; Tropanes

2014
Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity.
    Journal of medicinal chemistry, 2011, Feb-24, Volume: 54, Issue:4

    Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

    Topics: Cell Line; Fibroblasts; Gaucher Disease; Glucosylceramidase; Humans; Hymecromone; Immunohistochemistry; Lysosomes; Magnetic Resonance Spectroscopy; Microscopy, Confocal; Molecular Chaperones; Quinazolines; Spectrometry, Mass, Electrospray Ionization; Spleen; Structure-Activity Relationship

2011
Synthesis of N-alkylated noeurostegines and evaluation of their potential as treatment for Gaucher's disease.
    Bioorganic & medicinal chemistry letters, 2011, Mar-01, Volume: 21, Issue:5

    The potent and selective inhibitor of β-glucosidases, noeurostegine, was evaluated as an inhibitor of glucocerebrosidase (GCase) to give an IC(50) value of 0.4 μM, being 250- and 150-fold better than N-butyl and N-nonyl noeurostegine, respectively. The parent noeurostegine and its N-butyl and N-nonyl alkylated congeners were also tested as pharmacological chaperones against a N370S GCase mutant. Of these, only noeurostegine, was found to increase enzyme activity, which in potency was comparable to that previously reported for isofagomine.

    Topics: Enzyme Assays; Gaucher Disease; Glucosylceramidase; Humans; Inhibitory Concentration 50; Nortropanes

2011
In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.
    Bioorganic & medicinal chemistry, 2008, Aug-01, Volume: 16, Issue:15

    We investigated in vitro inhibition of mammalian carbohydrate-degrading enzymes by six-membered sugar mimics and their evaluation in cell cultures. 1-Deoxynojirimycin (DNJ) showed no significant inhibition toward glycogen phosphorylase (GP) but was a potent inhibitor of another glycogen-degrading enzyme, amylo-1,6-glucosidase (1,6-GL), with an IC(50) value of 0.16 microM. In primary rat hepatocytes, the inhibition of glycogen breakdown by DNJ reached plateau at 100 microM with 25% inhibition and then remained unchanged. The potent GP inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1) inhibited hepatic glucose production with an IC(50) value of about 9 microM and the inhibition by D-AB1 was further enhanced in the presence of DNJ. DNJ and alpha-homonojirimycin (HNJ) are very potent inhibitors of rat intestinal maltase, with IC(50) values of 0.13 and 0.08 microM, respectively, and also showed a similar strong inhibition toward maltase in Caco-2 cell model system, with IC(50) value of 0.05 and 0.10 microM, respectively. D-Isofagomine (D-IFG) and L-IFG are competitive and noncompetitive inhibitors of human lysosomal beta-glucosidase (beta-GL), respectively, with K(i) values of 8.4 nM and 6.9 microM. D-IFG increased intracellular beta-GL activity by twofold at 10 microM in Gaucher N370S cell line as an 'active-site-specific' chaperone, and surprisingly a noncompetitive inhibitor L-IFG also increased intracellular beta-GL activity by 1.6-fold at 500 microM.

    Topics: Animals; Caco-2 Cells; Carbohydrate Conformation; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Gaucher Disease; Glycogen; Glycoside Hydrolases; Hepatocytes; Humans; Imino Sugars; Lysosomes; Rats; Structure-Activity Relationship

2008
Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.
    Nature chemical biology, 2007, Volume: 3, Issue:2

    Gaucher disease results from mutations in the lysosomal enzyme acid beta-glucosidase (GCase). Although enzyme replacement therapy has improved the health of some affected individuals, such as those with the prevalent N370S mutation, oral treatment with pharmacological chaperones may be therapeutic in a wider range of tissue compartments by restoring sufficient activity of endogenous mutant GCase. Here we demonstrate that isofagomine (IFG, 1) binds to the GCase active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. We also compare the crystal structures of IFG-bound GCase at low pH with those of glycerol-bound GCase at low pH and apo-GCase at neutral pH. Our data indicate that IFG induces active GCase, which is secured by interactions with Asn370. The design of small molecules that stabilize substrate-bound conformations of mutant proteins may be a general therapeutic strategy for diseases caused by protein misfolding and mistrafficking.

    Topics: Catalytic Domain; Crystallography, X-Ray; Enzyme Inhibitors; Fibroblasts; Gaucher Disease; Glucosylceramidase; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Imino Pyranoses; Models, Molecular; Piperidines; Protein Binding; Protein Conformation; Protein Transport

2007