title: AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics.
abstract: A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.
authors.affiliation: AstraZeneca Translational Sciences Centre, Science for Life Laboratory, Personal Healthcare and Biomarkers, AstraZeneca, Solna, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.affiliation: AstraZeneca Translational Sciences Centre, Science for Life Laboratory, Personal Healthcare and Biomarkers, AstraZeneca, Solna, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.affiliation: Discovery Science iMed, AstraZeneca, Mölndal, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Kaspersson
authors.affiliation: AstraZeneca Translational Sciences Centre, Science for Life Laboratory, Personal Healthcare and Biomarkers, AstraZeneca, Solna, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Bogstedt
authors.affiliation: CNS and Pain iMed, AstraZeneca, Södertälje, Sweden.|Operations Global Quality, AstraZeneca, Södertälje, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.affiliation: CNS and Pain iMed, AstraZeneca, Södertälje, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.affiliation: Neuroscience iMed, IMED Biotech Unit, AstraZeneca, Cambridge, MA, USA.
authors.forename: Samantha Budd
authors.initials: SB
authors.lastname: Haeberlein
authors.affiliation: Neuroscience iMed, IMED Biotech Unit, AstraZeneca, Cambridge, MA, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Kugler
authors.affiliation: Neuroscience iMed, IMED Biotech Unit, AstraZeneca, Cambridge, MA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Alexander
authors.affiliation: Neuroscience iMed, IMED Biotech Unit, AstraZeneca, Cambridge, MA, USA.
authors.forename: Gvido
authors.initials: G
authors.lastname: Cebers
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001774:Blood Chemical Analysis; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D013141:Spiro Compounds; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; C000608388:lanabecestat
keywords: Alzheimer’s disease; amyloid-β; drug therapy; pharmacology; preclinical drug evaluation