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Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2001
Contact PI Name:
Dale B. Schenk
Contact PI Affiliation:
Elan Pharmaceuticals, Inc., South San Francisco, California, USA
Co-Authors:
H.F. Dovey, V. John, J.P. Anderson, L.Z. Chen, P. de Saint Andrieu, L.Y. Fang, S.B. Freedman, B. Folmer, E. Goldbach, et al.,
Primary Reference (PubMED ID):
11145990
Funding Source:
Not Reported
Study Goal and Principal Findings:

The goal of this study is to investigate gamma-secretase inhibitors on beta-amyloid levels in brains of PDAPP mice. Gamma secretase is  known to cause carboxy-terminal cleavage of APP to produce Aβ, one of the primary causative agents in Alzheimer's disease. In this study, a novel class of small molecule inhibitors of gamma-secretase that block Aβ production in vitro were further investigated for in vivo gamma-secretase inhibition using PDAPP mice. Results showed after oral administration, one of the compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester,also known as DAPT, reduced brain Aβ in a dose-dependent manner within 3 hours. Development of these gamma-secretase inhibitors will enable clinical examination into the Aβ hypothesis and could be potential therapeutics for Alzheimer's disease.

Bibliographic Notes:
Full Author List: H.F. Dovey, V. John, J.P. Anderson, L.Z. Chen, P. De Saint Andrieu, L.Y. Fang, S.B. Freedman, B. Folmer, E. Goldbach, E.J. Holsztynska, K.L. Hu, K.L. Johnson‐Wood, S.L. Kennedy, D. Kholodenko, J.E. Knops, L.H. Latimer, M. Lee, Z. Liao, I.M. Lieberburg, R.N. Motter, L.C. Mutter, J. Nietz, K.P. Quinn, K.L. Sacchi, P.A. Seubert, G.M. Shopp, E.D. Thorsett, J.S. Tung, J. Wu, S. Yang, C.T. Yin, D.B. Schenk, P.C. May, L.D. Altstiel, M.H. Bender, L.N. Boggs, T.C. Britton, J.C. Clemens, D.L. Czilli, D.K. Dieckman‐McGinty, J.J. Droste, K.S. Fuson, B.D. Gitter, P.A. Hyslop, E.M. Johnstone, W‐Y. Li, S.P. Little, T.E. Mabry, F.D. Miller, B. Ni, J.S. Nissen, W.J. Porter, B.D. Potts, J.K. Reel, D. Stephenson, Y. Su, L.A. Shipley, C.A. Whitesitt, T. Yin, J.E. Audia.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
DAPT
PubMed
PubChem
Patents
Therapeutic Target:
gamma Secretase
Open Targets
Pharos

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
PDAPP(line109)
ALZFORUM
Strain/Genetic Background:
Not Reported

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
Brain-beta Amyloid Peptide-Total
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP)
APP-CTFs
Soluble Amyloid Precursor Protein alpha (sAPP alpha)
Soluble Amyloid Precursor Protein beta (sAPP beta)
Pharmacokinetics
Drug Concentration-Brain
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
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