title: Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer's Disease.
abstract: A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Frederik J R
authors.identifier: 0000-0003-1986-0476
authors.initials: FJ
authors.lastname: Rombouts
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: José-Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ariza
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Alonso
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Nigel
authors.initials: N
authors.lastname: Austin
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Astrid
authors.initials: A
authors.lastname: Bottelbergs
authors.affiliation: Isotope Chemistry and Biotransformation, Janssen Research & Development , Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chupakhin
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Erna
authors.initials: E
authors.lastname: Cleiren
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: Fierens
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Leenaerts
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mariën
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Carolina
authors.initials: C
authors.lastname: Martínez Lamenca
authors.affiliation: Isotope Chemistry and Biotransformation, Janssen Research & Development , Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
authors.forename: Rhys
authors.initials: R
authors.lastname: Salter
authors.affiliation: Neuroscience Experimental Medicine, Janssen Early Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Paula
authors.initials: P
authors.lastname: Te Riele
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wintmolders
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Andrés A
authors.identifier: 0000-0002-4225-758X
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: Neuroscience Biomarker Research, Janssen Research & Development , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D000586:Amination; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D000882:Haplorhini; D006801:Humans; D051379:Mice; D009287:Naphthyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D066263:Protein Aggregation, Pathological / Q000000981:diagnostic imaging*; D051381:Rats; D016875:tau Proteins / Q000032:analysis*
chemical_list: D016229:Amyloid beta-Peptides; D009287:Naphthyridines; D016875:tau Proteins