Bibliographic
Year of Publication:
2013
Contact PI Name:
Susanna Eketjall
Primary Reference (PubMED ID):
Funding Source:
AstraZeneca Research and Development Innovative Medicines CNS and Pain Sweden
Study Goal and Principal Findings:
In this study the authors report the discovery, pharmacokinetic and pharmacodynamic properties of the BACE1 inhibitor AZ-4217, a high potency compound with an excellent in vivo efficacy. The efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in the Tg2576 mouse model of cerebral amyloidosis (Tg2576). In addition, data show that a 1 month treatment paradigm, in 12-month-old Tg2576 mice, is sufficient to significantly reduce beta-amyloid deposition. These results strongly support BACE1 inhibition as concretely impacting beta-amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.
Therapeutic Agent
Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
AZ-4217
Therapeutic Target:
BACE1
Animal Model
Model Information:
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57BL/6
Species:
Guinea Pig
Model Type:
Outbred
Model Name:
Dunkin-Hartley
Strain/Genetic Background:
Not Applicable
Experimental Design
Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Outcomes
Outcome Measured
Outcome Parameters
Biochemical
Soluble Amyloid Precursor Protein beta (sAPP beta)
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
CSF-beta Amyloid Peptide 40
Amyloid Precursor Protein (APP) Metabolites
Plasma-beta Amyloid Peptide 40
Pharmacokinetics
Drug Concentration-Brain
Cmax
Clearance (L/h/kg)
PK/PD Modeling
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
Target Engagement (Reduction Soluble Amyloid Precursor Protein beta)
Target Engagement (Increased Soluble Amyloid Precursor Protein alpha)
Biomarker
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
CSF-beta Amyloid Peptide 40
ADME
Plasma Protein Binding