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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Jan 08; Vol. 58 (1), pp. 480-511. Date of Electronic Publication: 2014 Dec 03. - Publication Year :
- 2015
-
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.
- Subjects :
- Adenosine chemistry
Adenosine metabolism
Animals
Cells, Cultured
Class I Phosphatidylinositol 3-Kinases chemistry
Class I Phosphatidylinositol 3-Kinases metabolism
Crystallography, X-Ray
Disease Models, Animal
Drug Discovery
Female
Humans
Mice, Inbred BALB C
Mice, Transgenic
Models, Chemical
Models, Molecular
Molecular Structure
Protein Binding
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors metabolism
Protein Structure, Tertiary
Quinolines chemistry
Quinolines metabolism
Rats, Inbred Lew
Sf9 Cells
Structure-Activity Relationship
Adenosine pharmacology
Autoimmune Diseases prevention & control
Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors
Inflammation prevention & control
Protein Kinase Inhibitors pharmacology
Quinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25469863
- Full Text :
- https://doi.org/10.1021/jm501624r