title: 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.
abstract: 1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Frederik J R
authors.initials: FJ
authors.lastname: Rombouts
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Delgado
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Carolina
authors.initials: C
authors.lastname: Martínez-Lamenca
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Gool
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: García-Molina
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Alonso de Diego
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oehlrich
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Hana
authors.initials: H
authors.lastname: Prokopcova
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen-Cilag SA , 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 NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Nigel
authors.initials: N
authors.lastname: Austin
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Borghys
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Van Brandt
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Surkyn
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: De Cleyn
authors.affiliation: Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Vos
authors.affiliation: Biologics Research, Janssen Research & Development , 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Alexander
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.affiliation: Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Harrie
authors.initials: H
authors.lastname: Gijsen
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA , C/Jarama 75A, 45007 Toledo, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010078:Oxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D010078:Oxazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse