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 IC50 of 1−57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC50 = 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.
Design, Synthesis, and Structure−Activity Relationship of N‑Arylnaphthylamine Derivatives as Amyloid Aggregation Inhibitors / DI SANTO, Roberto; Costi, Roberta; CUZZUCOLI CRUCITTI, Giuliana; Pescatori, Luca; Rosi, Federica; Scipione, Luigi; Diana, Celona; Mario, Vertechy; Orlando, Ghirardi; Paola, Piovesan; Mauro, Marzi; Silvio, Caccia; Giovanna, Guiso; Fabrizio, Giorgi; Patrizia, Minetti. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 55(19):(2012), pp. 8538-8548. [10.1021/jm301105m]
Design, Synthesis, and Structure−Activity Relationship of N‑Arylnaphthylamine Derivatives as Amyloid Aggregation Inhibitors
DI SANTO, Roberto;COSTI, Roberta;CUZZUCOLI CRUCITTI, GIULIANA;PESCATORI, LUCA;ROSI, FEDERICA;SCIPIONE, Luigi;
2012
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 IC50 of 1−57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC50 = 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
