title: Design, synthesis, and structure-activity relationship of N-arylnaphthylamine derivatives as amyloid aggregation inhibitors.
abstract: Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 μM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, P.le A. Moro 5, I-00185 Roma, Italy. roberto.disanto@uniroma1.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cuzzucoli Crucitti
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.forename: Federica
authors.initials: F
authors.lastname: Rosi
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.forename: Diana
authors.initials: D
authors.lastname: Celona
authors.forename: Mario
authors.initials: M
authors.lastname: Vertechy
authors.forename: Orlando
authors.initials: O
authors.lastname: Ghirardi
authors.forename: Paola
authors.initials: P
authors.lastname: Piovesan
authors.forename: Mauro
authors.initials: M
authors.lastname: Marzi
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giorgi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009281:Naphthalenes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)