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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.

Authors :
Cushing TD
Hao X
Shin Y
Andrews K
Brown M
Cardozo M
Chen Y
Duquette J
Fisher B
Gonzalez-Lopez de Turiso F
He X
Henne KR
Hu YL
Hungate R
Johnson MG
Kelly RC
Lucas B
McCarter JD
McGee LR
Medina JC
San Miguel T
Mohn D
Pattaropong V
Pettus LH
Reichelt A
Rzasa RM
Seganish J
Tasker AS
Wahl RC
Wannberg S
Whittington DA
Whoriskey J
Yu G
Zalameda L
Zhang D
Metz DP
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.

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