title: Carbazole-containing arylcarboxamides as BACE1 inhibitors.
abstract: 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.
authors: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Simone
authors: S
authors: Bertini
authors: Valentina
authors: V
authors: Asso
authors: Elisa
authors: E
authors: Ghilardi
authors: Carlotta
authors: C
authors: Granchi
authors: Clementina
authors: C
authors: Manera
authors: Filippo
authors: F
authors: Minutolo
authors: Giuseppe
authors: G
authors: Saccomanni
authors: Andrea
authors: A
authors: Bortolato
authors: Jonathan
authors: J
authors: Mason
authors: Stefano
authors: S
authors: Moro
authors: Marco
authors: M
authors: Macchia
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002227:Carbazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002227:Carbazoles; D004791:Enzyme Inhibitors; C041514:carbazole; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human