4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors
Bibliographic
Year of Publication:
2006
Contact PI Name:
Ian Churcher
Primary Reference (PubMED ID):
Funding Source:
Merck Research Laboratories
Study Goal and Principal Findings:
The protease γ-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease. Here, they report a further extension to a series of cyclohexyl sulfone-based γ-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Ab(40) lowering in vivo (e.g., compound 32, MED 1 mg/kg p.o. in APP-YAC mice).
Therapeutic Agent
Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Target:
gamma Secretase
Animal Model
Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
APPSweLon
Strain/Genetic Background:
Not Reported
Animal Model Notes:
See Lamb et al 1993 (https://pubmed.ncbi.nlm.nih.gov/8220418/) for development and characterization of the APPSweLon transgenic mouse model.
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
Cell Biology
beta Amyloid Peptide Secretion
gamma Secretase Inhibition
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)
ADME
Metabolic Stability
Microsomal Stability
Biochemical
Brain-Detergent Soluble beta Amyloid Peptide 40