Carbazole-containing arylcarboxamides as BACE1 inhibitors
2011
Bertini, Simone | Asso, Valentina | Ghilardi, Elisa | Granchi, Carlotta | Manera, Clementina | Minutolo, Filippo | Saccomanni, Giuseppe | Bortolato, Andrea | Mason, Jonathan | Moro, Stefano | Macchia, Marco
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 (IC₅₀=3.8μM) or a 3,4-dichloro substituent (IC₅₀=2.5μM) 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.
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