Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase

Abstract

Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene (GBA1, GCase) that have been also linked to increased risk of Parkinson's disease 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 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 non-inhibitory GCase modulators in Parkinson's disease and related synucleinopathies.

The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers

“…In these models, S-181 partially restored lysosomal function and lowered the accumulation of oxidized dopamine, GluCer, and α-synuclein. Similar findings were also obtained treating mice carrying GBA heterozygous mutations [36].…”

Hydrogen peroxide-mediated synthesis of 2,4-substituted quinazolines via one-pot three-component reactions under metal-free conditions

“…Coupling with aliphatic aldehydes was also feasible, yielding 2,4-dialkylsubstituted quinazolines 3ae, 3ag, 3ah in good yields (entries 5-7). Next, 1-(6-aminobenzo[d] [1,3]dioxol-5-yl)ethan-1one was employed for the reaction with different aldehydes, producing 3ba, 3bb, 3bc, and 3bd in 74%, 78%, 75%, and 72% yields, respectively (entries 8-11). Moving to the transformation of 1-(2-amino-4,5-dimethoxyphenyl)ethan-1-one with several aldehydes, 3ca, 3cb, 3cc, and 3cd were generated in 72%, 70%, 75%, and 69% yields, respectively (entries 12-15).…”

“…Quinazolines and their derivatives are a privileged class of nitrogen-containing heterocyclic compounds, normally occurring in a variety of natural products and synthetic chemicals with a wide spectrum of biological and medicinal activities. [1][2][3][4] Due to their pharmaceutical applications and signicant biological value, a variety of methodologies have been explored for the synthesis of these structures. Typical approaches started from ortho-functionalized anilines and derivatives, such as 2-carbonyl anilines, 5 2-aminobenzylamines, 6 and 2-aminobenzonitriles.…”

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

“…The recent co-crystallization of the Gcase with a quinazoline derivative not only helped to understand the mechanism of non-iminosugar inhibitory PC but also allowed the discovery of an allosteric binding site which could be responsive to activators (PDB code 5LVX) [ 63 ]. Thanks to a broad structure-activity relationship study in this compound series [ 62 , 64 ], Silvermann et al, recently found that N -methylation of some of the quinazoline inhibitors derivatives turned them into activators. Compound S-181 (( S )- N -((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)- N -methyl-2-(pyridin-3-yl)quinazolin-4-amine, Table 1 ) was highlighted as the most potent non-inhibitory Gcase PC with specificity towards the Gcase and not α-glucosidases or galactosidases [ 64 ].…”