title: 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.affiliation: Department of Therapeutic Discovery, ‡Department of Pharmacokinetics and Drug Metabolism, and §Department of Pharmaceutics Research and Development, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Kristin
authors.initials: K
authors.lastname: Andrews
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jason
authors.initials: J
authors.lastname: Duquette
authors.forename: Ben
authors.initials: B
authors.lastname: Fisher
authors.forename: Felix
authors.initials: F
authors.lastname: Gonzalez-Lopez de Turiso
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Henne
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hu
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Ron C
authors.initials: RC
authors.lastname: Kelly
authors.forename: Brian
authors.initials: B
authors.lastname: Lucas
authors.forename: John D
authors.initials: JD
authors.lastname: McCarter
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: Deanna
authors.initials: D
authors.lastname: Mohn
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Jennifer
authors.initials: J
authors.lastname: Seganish
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Sharon
authors.initials: S
authors.lastname: Wannberg
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: John
authors.initials: J
authors.lastname: Whoriskey
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Metz
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011917:Rats, Inbred Lew; D061987:Sf9 Cells; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; C000597234:N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D000241:Adenosine