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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

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journal contribution
posted on 08.01.2015, 00:00 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. Metz
The 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.