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

Jianbin Zheng, Sohee Jeon, Weilan Jiang, Lena F. Burbulla, Daniel Ysselstein, Kristine Oevel, Dimitri Krainc*, Richard B. Silverman

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1218-1230
Number of pages13
JournalJournal of Medicinal Chemistry
Volume62
Issue number3
DOIs
StatePublished - Feb 14 2019

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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