title: Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays.
abstract: 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.
authors.affiliation: INSERM U-623, IBDM, Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France.
authors.forename: Cédrik
authors.initials: C
authors.lastname: Garino
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
authors.forename: Younes
authors.initials: Y
authors.lastname: Laras
authors.forename: Roselyne
authors.initials: R
authors.lastname: Rosas
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Herbette
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
authors.forename: Gilles
authors.initials: G
authors.lastname: Quéléver
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
mesh_terms: 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
chemical_list: 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