title: Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).
abstract: Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Felix
authors.initials: F
authors.lastname: Gonzalez-Lopez de Turiso
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Minna
authors.initials: M
authors.lastname: Bui
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Iain D G
authors.initials: ID
authors.lastname: Campuzano
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Dunn
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Duquette
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fisher
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Kirk
authors.initials: K
authors.lastname: Henne
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hu
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Ron C
authors.initials: RC
authors.lastname: Kelly
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lucas
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: John
authors.initials: J
authors.lastname: McCarter
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Daniela
authors.initials: D
authors.lastname: Metz
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Deanna
authors.initials: D
authors.lastname: Mohn
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Vissinga
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wannberg
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: John
authors.initials: J
authors.lastname: Whoriskey
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.|Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620115:2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide; C000620114:2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011804:Quinolines; D058543:Class Ia Phosphatidylinositol 3-Kinase