title: Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
abstract: 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.
authors.affiliation: Research and Development, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peretto
authors.forename: Stefano
authors.initials: S
authors.lastname: Radaelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Parini
authors.forename: Michele
authors.initials: M
authors.lastname: Zandi
authors.forename: Luca F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Laura
authors.initials: L
authors.lastname: Fontanella
authors.forename: Paola
authors.initials: P
authors.lastname: Misiano
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.forename: Benedetta
authors.initials: B
authors.lastname: Riccardi
authors.forename: Marcello
authors.initials: M
authors.lastname: Biscaioli
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchetti
authors.forename: Paola
authors.initials: P
authors.lastname: Puccini
authors.forename: Silvia
authors.initials: S
authors.lastname: Catinella
authors.forename: Ivano
authors.initials: I
authors.lastname: Rondelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Cenacchi
authors.forename: Pier Tonino
authors.initials: PT
authors.lastname: Bolzoni
authors.forename: Paola
authors.initials: P
authors.lastname: Caruso
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Elda
authors.initials: E
authors.lastname: Del Giudice
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen