isofagomine has been researched along with Parkinson-Disease* in 2 studies
2 other study(ies) available for isofagomine and Parkinson-Disease
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Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.
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.
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 |