Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid 1-42 secretion

Bibliographic

Year of Publication: 
2005
Contact PI Name: 
Bruno P. Imbimbo
Contact PI Affiliation: 
Research and Development, Chiesi Farmaceutici S.p.A., Parma, Italy
Co-Authors: 
I. Peretto, S. Radaelli, C. Parini, M. Zandi, L.F. Raveglia, G. Dondio, L. Fontanella, P. Misiano, C. Bigogno, A. Rizzi, et al.,
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

The study screened a library of NSAID flurbiprofen mimics to find selective inhibitors of Aβ secretion. Epidemiological studies have documented a reduced prevalence of AD among patients using NSAIDs. Despite these encouraging findings, all large, long-term, placebo controlled clinical trials aimed at reducing inflammation in the brain of AD patients have produced negative results. More recently, it has been shown that some NSAIDs decrease the production of Aβ42 in vitro and in vivo and counteract the progression of Aβ42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of PS-1, the major component of the γ-secretase complex, the enzyme responsible for the formation of Aβ.  The inhibition of Aβ42 production is independent of the anti-cyclooxygenase activity and is related to the chemical structure of the compounds. Unfortunately, the generic use of NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. This study tried to identify new NSAIDs analogues endowed with potent and selective Aβ42 lowering activity but devoid of COX inhibitory activity, thus suitable for chronic use in AD patients. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency onAβ42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Aβ42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD. 

Bibliographic Notes: 
Full Author List: Ilaria Peretto, Stefano Radaelli, Carlo Parini, Michele Zandi, Luca F. Raveglia, Giulio Dondio, Laura Fontanella, Paola Misiano, Chiara Bigogno, Andrea Rizzi, Benedetta Riccardi, Marcello Biscaioli, Silvia Marchetti, Paola Puccini, Silvia Catinella, Ivano Rondelli, Valentina Cenacchi, Pier Tonino Bolzoni, Paola Caruso, Gino Villetti, Fabrizio Facchinetti, Elda Del Giudice, Nadia Moretto, Bruno P. Imbimbo.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
B6SJLF1
Animal Model Notes: 
Pharmacokinetic studies were performed in rats. However, no information is provided on the strain of the rats used.

Experimental Design

Is the following information reported in the study?: 
Power/Sample Size Calculation
Blinded for Treatment
Pharmacokinetic Measures
Toxicology Measures
Biomarkers
Formulation
Duration of Treatment
Age of Animal at the Beginning of Treatment
Sex as a Biological Variable
Number of Premature Deaths
Statistical Plan
Inclusion/Exclusion Criteria Included
Randomized into Groups
Blinded for Outcome Measures
Pharmacodynamic Measures
ADME Measures
Dose
Route of Delivery
Frequency of Administration
Age of Animal at the End of Treatment
Study Balanced for Sex as a Biological Variable
Number of Excluded Animals
Genetic Background
Conflict of Interest

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Biochemical
  • Cyclooxygenase 1 (COX 1) activity
  • Cyclooxygenase 2 (COX 2) Activity
  • gamma Secretase
  • Notch Selectivity
  • Brain-beta Amyloid Peptide 38
  • Brain-beta Amyloid Peptide 40
  • Brain-beta Amyloid Peptide 42
  • Biomarker
  • Plasma-beta Amyloid Peptide 40
  • Plasma-beta Amyloid Peptide 42
  • Pharmacokinetics
  • Drug Concentration-Plasma
  • Tmax
  • Drug Concentration-CSF
  • Oral Bioavailability (F%)
  • CSF/Plasma Ratio
  • Pharmacodynamics
  • Target Engagement (Reduction beta Amyloid Peptides-Plasma)
  • Toxicology
  • Toxicity-Gastrointestinal (GI)
  • Cell Viability
  • Morbidity
  • Body Weight
  • ADME
  • Body Clearance
  • CYP450 Inhibition
  • Drug Permeability
  • Metabolic Stability