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.
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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)
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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
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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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