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.
Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.|Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University , Evanston, Illinois 60208-3113, United States.
Jianbin
J
Zheng
Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
Long
L
Chen
Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
Michael
M
Schwake
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University , Evanston, Illinois 60208-3113, United States.
Richard B
RB
Silverman
Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
Dimitri
D
Krainc
D002460:Cell Line; D015195:Drug Design; D004795:Enzyme Stability / Q000187:drug effects; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*
D011799:Quinazolines; D005962:Glucosylceramidase