title: AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice.
abstract: Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.
authors.affiliation: Innovative Medicines AstraZeneca, CNS & Pain, S-151 85 Södertälje, Sweden. Susanna.Eketjall@astrazeneca.com
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Alexander
authors.initials: A
authors.lastname: Svanhagen
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Susanne
authors.initials: S
authors.lastname: Gustavsson
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Radesäter
authors.forename: Kristina
authors.initials: K
authors.lastname: Eliason
authors.forename: Sveinn
authors.initials: S
authors.lastname: Briem
authors.forename: Paulina
authors.initials: P
authors.lastname: Appelkvist
authors.forename: Camilla
authors.initials: C
authors.lastname: Niva
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Berg
authors.forename: Sofia
authors.initials: S
authors.lastname: Karlström
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C583038:AZ-4217; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D054833:Isoindoles; D010446:Peptide Fragments; D011728:Pyridones; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human