Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. 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 on Abeta42 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 Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
Peretto
Ilaria
I
Research and Development, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy.
Radaelli
Stefano
S
Parini
Carlo
C
Zandi
Michele
M
Raveglia
Luca F
LF
Dondio
Giulio
G
Fontanella
Laura
L
Misiano
Paola
P
Bigogno
Chiara
C
Rizzi
Andrea
A
Riccardi
Benedetta
B
Biscaioli
Marcello
M
Marchetti
Silvia
S
Puccini
Paola
P
Catinella
Silvia
S
Rondelli
Ivano
I
Cenacchi
Valentina
V
Bolzoni
Pier Tonino
PT
Caruso
Paola
P
Villetti
Gino
G
Facchinetti
Fabrizio
F
Del Giudice
Elda
E
Moretto
Nadia
N
Imbimbo
Bruno P
BP
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005910:Glioma; D006801:Humans; D007118:Immunoassay; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen