Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators

Jianbin Zheng, Long Chen, Michael Schwake, Richard B. Silverman*, Dimitri Krainc

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8508-8520
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
DOIs
StatePublished - Sep 22 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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