Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Nicolas Pietrancosta; Gilles Quéléver; Younes Laras; Cédrik Garino; Stéphane Burlet; Jean Louis Kraus

doi:10.1071/CH05102

RESEARCH ARTICLE

Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Nicolas Pietrancosta ^A , Gilles Quéléver ^A , Younes Laras ^A , Cédrik Garino ^A , Stéphane Burlet ^A and Jean Louis Kraus ^A ^B

+ Author Affiliations

- Author Affiliations

^A INSERM U-623, Institut de Biologie du Développement de Marseille (CNRS–INSERM–Université de la Méditerranée), Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, case 907, 13288 Marseille Cedex 09, France.

^B Corresponding author. Email: kraus@luminy.univ-mrs.fr

Australian Journal of Chemistry 58(8) 585-594 https://doi.org/10.1071/CH05102
Submitted: 21 April 2005 Accepted: 17 June 2005 Published: 31 August 2005

Abstract

We report the synthesis of two series of compounds with 3,5-difluoromandelyl-alanyl or 3,5-difluorophenylacetyl-alanyl backbones coupled to various heterocyclic or peptidic moieties. These two series of compounds were evaluated for their inhibitory properties on β-secretase (BACE-1) enzymatic assay, a target enzyme for Alzheimer’s disease (AD) pathology. We found that both diastereomers obtained from the racemic mixture 7 of the coumarin derivative bearing a mandelyl moiety were the most potent BACE-1 inhibitors studied in this work (IC₅₀ = 1 × 10⁻⁶ M). Analysis of the obtained results led to the hypothesis that introduction of a difluoromandelyl residue in place of a difluorophenylacetyl moiety may induce β-secretase inhibitory activity.

Acknowledgments

INSERM and Conseil Régional Provence-Alpes-Côte d’Azur are greatly acknowledged for financial support (fellowships for N.P. and C.G.). We are grateful to Dr Philippe Pierre and members of his research team (CIML, Inserm-CNRS, Université de la Méditerranée, France) for their assistance when we performed the spectrofluorimetric measurements for the BACE-1 (β-secretase) FRET assays. The authors thank Prof. Keith Dudley (INSERM U-623) for manuscript preparation.

References

Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Abstract

Acknowledgments

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