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AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice
- Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(24)
- Publication Year :
- 2013
-
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 (IC(50) 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.
- Subjects :
- Genetically modified mouse
Male
Amyloid
Time Factors
Pyridones
Transgene
Guinea Pigs
Mice, Transgenic
Pharmacology
Isoindoles
Amyloid beta-Protein Precursor
Mice
In vivo
Alzheimer Disease
mental disorders
Amyloid precursor protein
medicine
Potency
Animals
Aspartic Acid Endopeptidases
Humans
Enzyme Inhibitors
IC50
Cells, Cultured
Cerebral Cortex
Neurons
Amyloid beta-Peptides
biology
Dose-Response Relationship, Drug
Chemistry
General Neuroscience
Amyloidosis
P3 peptide
Articles
medicine.disease
Embryo, Mammalian
Peptide Fragments
Mice, Inbred C57BL
Disease Models, Animal
Mutation
biology.protein
Female
Amyloid Precursor Protein Secretases
Subjects
Details
- ISSN :
- 15292401
- Volume :
- 33
- Issue :
- 24
- Database :
- OpenAIRE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Accession number :
- edsair.doi.dedup.....5c92f198c1a255d3d4f750e538efd83e