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.
MeSH terms
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Adenosine / chemistry
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Adenosine / metabolism
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Adenosine / pharmacology*
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Animals
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Autoimmune Diseases / prevention & control*
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Cells, Cultured
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class I Phosphatidylinositol 3-Kinases / chemistry
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Discovery
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Female
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Humans
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Inflammation / prevention & control*
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Mice, Inbred BALB C
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Mice, Transgenic
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Protein Binding
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Structure, Tertiary
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Quinolines / chemistry
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Quinolines / metabolism
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Quinolines / pharmacology*
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Rats, Inbred Lew
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Sf9 Cells
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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Quinolines
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N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine
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Class I Phosphatidylinositol 3-Kinases
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PIK3CD protein, human
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Adenosine
Associated data
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PDB/4WWN
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PDB/4WWO
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PDB/4WWP