Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays.
Twenty novel beta-secretase inhibitors containing biarylpiperazine moieties belonging to naphthyl and coumarinyl series were designed for their potential use in Alzheimer's disease therapy. Enzymatic and cell-based assays have been carried out. The biological results clearly demonstrate that specific substituents located at the N(4)-position of the piperazine ring result in excellent in vitro inhibitory potency (IC(50) values ranging between 40 and 70 nM). Variable temperature NMR and modeling studies are consistent with the obtained biological data, since these studies confirmed that introduction at the N(4)-position of the piperazine ring allows productive interactions within the BACE-1 active site, which appear to be determinative for high BACE-1 inhibitory activity. These results are of particular interest since some of the new analogues belonging to the naphthyl series are almost one log more active than the best inhibitor of the similar family recently reported.
Garino
Cédrik
C
INSERM U-623, IBDM, Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France.
Tomita
Taisuke
T
Pietrancosta
Nicolas
N
Laras
Younes
Y
Rosas
Roselyne
R
Herbette
Gaëtan
G
Maigret
Bernard
B
Quéléver
Gilles
G
Iwatsubo
Takeshi
T
Kraus
Jean-Louis
JL
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003374:Coumarins; D009281:Naphthalenes; D010879:Piperazines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse