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1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity


Year of Publication:
Contact PI Name:
Bruno P. Imbimbo
Contact PI Affiliation:
Research and Development, Chiesi Farmaceutici, Parma, Italy
Elda Del Giudice, Davide Colavito, Antonello D’Arrigo, Maurizio Dalle Carbonare, Gino Villetti, Fabrizio Facchinetti, Roberta Volta
Primary Reference (PubMED ID):
Funding Source:
Chiesi Farmaceutici Parma Italy
Study Goal and Principal Findings:

The aim of this study is to determine the effects of chronic treatment with CHF5074, a novel gamma secretase modulator, on brain Abeta levels, and beta amyloid plaque deposition in the Tg2576 mouse model of AD. In addition, the authors examined peripheral Tg mouse tissue for signs of toxicity, in particular those that may be related to COX inhibition or altered Notch signaling.Twenty-eight Tg mice of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (52.2 5.6%, p = 0.0003 and 48.9 6.6%, p = 0.0004, respectively) and hippocampus (76.7 6.4%, p= 0.004 and 66.2 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (49.2 9.2%, p = 0.017) and Abeta42 (43.5 9.7%, p= 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta 42 and Abeta 40 secretion, with an IC50 of 3.6 and 18.4 uM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 uM). At 5 uM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No deaths occurred during the 17-week treatment period; body weight and body weight gain over time were very similar to those of the vehicle-treated group. At week 17, macroscopic and histological examinations of potential peripheral target organs did not show significant abnormalities. In the ileum, there were no differences in goblet cell numbers and distribution between the vehicle-dosed animals and the animals receiving CHF5074. The spleen of the CHF5074-treated animals did not show histological abnormalities. Finally, histological evaluation of other portions of the gastrointestinal tract revealed no abnormalities. Overall, the data demonstrate that chronic treatment with CHF5074 can significantly reduce the induction of amyloid deposits in the brains of Tg2576 mice without causing histopathological changes in peripheral organs that would be associated with inhibition of Notch processing by gamma secretase.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase

Animal Model

Model Information:
Model Type:
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
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


Outcome Measured
Outcome Parameters
beta Amyloid Deposits
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Notch Cleavage
Activated Astrocytes
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Drug Concentration-Plasma
Drug Concentration-Brain
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Body Weight
Systemic Tissue Histotoxicity