β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1.
|Autori:||Bertini S; Asso V; Ghilardi E; Granchi C; Manera C; Minutolo F; Saccomanni G; Bortolato A; Mason J; Moro S; Macchia M|
|Titolo:||Carbazole-containing arylcarboxamides as BACE1 inhibitors|
|Anno del prodotto:||2011|
|Digital Object Identifier (DOI):||10.1016/j.bmcl.2011.09.064|
|Appare nelle tipologie:||1.1 Articolo in rivista|