Naphthyl and Coumarinyl Biarylpiperazine Derivatives as Highly Potent Human β-Secretase Inhibitors. Design, Synthesis, and Enzymatic BACE-1 and Cell Assays

Cédrik Garino (1) , Taisuke Tomita (2) , Nicolas Pietrancosta (3, 4) , Younes Laras (1) , Roselyne Rosas (5) , Gaëtan Herbette (5) , Bernard Maigret (6) , Gilles Quéléver (7) , Takeshi Iwatsubo (2) , Jean-Louis Kraus (7)

1 IBDM - Institut de Biologie du Développement de Marseille
2 UTokyo - The University of Tokyo
3 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
4 LBM UMR 7203 - Laboratoire des biomolécules
5 AMU SPEC - Spectropôle - Aix Marseille Université
6 CAPSID - Computational Algorithms for Protein Structures and Interactions
7 Rétrovirus et Maladies Associées

Twenty novel â-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 N4-position of the piperazine ring result in excellent in vitro inhibitory potency (IC50 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 N4-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.

Domaines: Chimie thérapeutique

Cédrik Garino, Taisuke Tomita, Nicolas Pietrancosta, Younes Laras, Roselyne Rosas, et al.. Naphthyl and Coumarinyl Biarylpiperazine Derivatives as Highly Potent Human β-Secretase Inhibitors. Design, Synthesis, and Enzymatic BACE-1 and Cell Assays. Journal of Medicinal Chemistry, 2006, 49 (14), pp.4275-4285. ⟨10.1021/jm0602864⟩. ⟨hal-02351696⟩