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Discovery and in Vivo Evaluation of (S)‑N‑(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)‑9H‑purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease
journal contribution
posted on 2015-01-08, 00:00 authored by Timothy D. Cushing, Xiaolin Hao, Youngsook Shin, Kristin Andrews, Matthew Brown, Mario Cardozo, Yi Chen, Jason Duquette, Ben Fisher, Felix Gonzalez-Lopez de Turiso, Xiao He, Kirk R. Henne, Yi-Ling Hu, Randall Hungate, Michael
G. Johnson, Ron C. Kelly, Brian Lucas, John D. McCarter, Lawrence R. McGee, Julio
C. Medina, Tisha San Miguel, Deanna Mohn, Vatee Pattaropong, Liping H. Pettus, Andreas Reichelt, Robert M. Rzasa, Jennifer Seganish, Andrew
S. Tasker, Robert C. Wahl, Sharon Wannberg, Douglas A. Whittington, John Whoriskey, Gang Yu, Leeanne Zalameda, Dawei Zhang, Daniela
P. MetzThe development and optimization
of a series of quinolinylpurines
as potent and selective PI3Kδ kinase inhibitors with excellent
physicochemical properties are described. This medicinal chemistry
effort led to the identification of 1 (AMG319), a compound
with an IC50 of 16 nM in a human whole blood assay (HWB),
excellent selectivity over a large panel of protein kinases, and a
high level of in vivo efficacy as measured by two rodent disease models
of inflammation.
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quinolinylpurineseriesrodent disease modelsIC 50Autoimmune DiseaseThe developmentblood assayVivo Evaluationchemistry effortHWBAMGidentificationinflammation16 nMvivo efficacycompoundprotein kinasespanelselectivityPI 3K kinase inhibitorsRelated PI 3K Inhibitorsoptimizationphysicochemical propertiesInflammation
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