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Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2009
Contact PI Name:
J. Steven Jacobsen
Contact PI Affiliation:
Wyeth Research, Departments of Discovery Neuroscience, Princeton, New Jersey, USA
Co-Authors:
Robert L. Martone, Hua Zhou, Kevin Atchison, Thomas Comery, Jane Z. Xu, Xinyi Huang, Xioahai Gong, Mei Jin, Anthony Kreft, Boyd Harrison, et al.,
Primary Reference (PubMED ID):
19671883
Funding Source:
Wyeth Research
Study Goal and Principal Findings:

 Gamma secretase is widely regarded as a viable target to achieve therapeutically relevant reductions of Aβ in AD, and multiple classes of GSIs have been reported including peptidomimetics and sulfonamides. The goal of this study was to report on the pharmacological properties of  the novel thiophene sulfonamide gamma secretase inhibitor (GSI), GSI-953,also known as begacestat.In summary, the preclinical data for GSI-953 demonstrate a potent Abeta lowering activity, with nano molar potency,  and in vitro selectivity against Notch processing. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In addition, the drug exhibited robust in vivo efficacy for the lowering of brain, CSF, and plasma Abeta levels and the reversal of Abeta-dependent cognitive deficits in Tg2576 mice. Finally the drug was found lower of plasma Abeta ( a potential biomarker) levels in humans. These data provide evidence supporting  GSI-953  treatment as a potential  disease modification in the development of AD.

Bibliographic Notes:
Full Author List: Robert L. Martone, Hua Zhou, Kevin Atchison, Thomas Comery, Jane Z. Xu, Xinyi Huang, Xioahai Gong, Mei Jin, Anthony Kreft, Boyd Harrison, Scott C. Mayer, Suzan Aschmies, Cathleen Gonzales, Margaret M. Zaleska, David R. Riddell, Erik Wagner, Peimin Lu, Shaiu-Ching Sun, June Sonnenberg-Reines, Aram Oganesian, Karissa Adkins, Michael W. Leach, David W. Clarke, Donna Huryn, Magid Abou-Gharbia, Ronald Magolda, Jonathan Bard, Glen Frick, Sangeeta Raje, S. Bradley Forlow, Carrie Balliet, Michael E. Burczynski, Peter H. Reinhart, Hong I. Wan, Menelas N. Pangalos, J. Steven Jacobsen.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
GSI-953 (Begacestat)
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
gamma Secretase
Open Targets
Pharos

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
Tg2576
ALZFORUM
Strain/Genetic Background:
Not Reported
Species:
Rat
Model Type:
Outbred
Model Name:
Sprague Dawley
Strain/Genetic Background:
Not Applicable
Species:
Dog
Model Type:
Non-transgenic
Model Name:
Beagle
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
Experiment Notes

Toxicology studies in rats were balanced for gender. Gender was not reported for Tg2576 mouse efficacy studies (behavior and beta amyloid outcome measures).

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Contextual Fear Conditioning
Biochemical
Notch Selectivity
gamma Secretase Inhibition
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
Biomarker
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
Pharmacokinetics
Cmax
Area Under the Curve (AUC)
Brain/Plasma Ratio
PK/PD Modeling
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Toxicology
Tissue Histopathological Profile
Body Weight
Mortality
General Behavior
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