Design, synthesis, and structure-activity relationship of N-arylnaphthylamine derivatives as amyloid aggregation inhibitors.

Roberto Di Santo (1) , Roberta Costi (1) , Giuliana Cuzzucoli Crucitti (1) , Luca Pescatori (1) , Federica Rosi (1) , Luigi Scipione (1) , Diana Celona (2) , Mario Vertechy (2) , Orlando Ghirardi (2) , Paola Piovesan (2) , Mauro Marzi (2) , Silvio Caccia (3) , Giovanna Guiso (3) , Fabrizio Giorgi (2) , Patrizia Minetti (2)

1 Department of Medicinal Chemistry and Technologies
2 Sigma-Tau S.p.A.
3 Dipartimento di Neuroscienze

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.

Domains: Life Sciences [q-bio]; Pharmaceutical sciences

Roberto Di Santo, Roberta Costi, Giuliana Cuzzucoli Crucitti, Luca Pescatori, Federica Rosi, et al.. Design, synthesis, and structure-activity relationship of N-arylnaphthylamine derivatives as amyloid aggregation inhibitors.. Journal of Medicinal Chemistry, 2012, 55 (19), pp.8538-48. ⟨10.1021/jm301105m⟩. ⟨pasteur-00968739⟩