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 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 contribute

SUBMITTER: Zheng J 

PROVIDER: S-EPMC6467782 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature