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.

Abstract	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.
Authors	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
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 1 Pg. 480-511 (Jan 08 2015) ISSN: 1520-4804 [Electronic] United States
PMID	25469863 (Publication Type: Journal Article)
Chemical References	Protein Kinase Inhibitors Quinolines N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine Class I Phosphatidylinositol 3-Kinases PIK3CD protein, human Adenosine
Topics	Adenosine (chemistry, metabolism, pharmacology) Animals Autoimmune Diseases (prevention & control) Cells, Cultured Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, chemistry, metabolism) Crystallography, X-Ray Disease Models, Animal Drug Discovery Female Humans Inflammation (prevention & control) Mice, Inbred BALB C Mice, Transgenic Models, Chemical Models, Molecular Molecular Structure Protein Binding Protein Kinase Inhibitors (chemistry, metabolism, pharmacology) Protein Structure, Tertiary Quinolines (chemistry, metabolism, pharmacology) Rats, Inbred Lew Sf9 Cells Structure-Activity Relationship

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