From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold

Angela Rampa; Francesca Mancini; Angela De Simone; Federico Falchi; Federica Belluti; Rita Maria Concetta Di Martino; Silvia Gobbi; Vincenza Andrisano; Andrea Tarozzi; Manuela Bartolini; Andrea Cavalli; Alessandra Bisi

doi:10.1016/j.bmcl.2015.05.002

From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold

Bioorg Med Chem Lett. 2015 Jul 15;25(14):2804-8. doi: 10.1016/j.bmcl.2015.05.002. Epub 2015 May 9.

Affiliations

¹ Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy. Electronic address: [email protected].
² Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
³ Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
⁴ Unit of Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy.
⁵ Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy; Unit of Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy.

PMID: 26003339
DOI: 10.1016/j.bmcl.2015.05.002

Abstract

In recent years, a progressive increase in age-related disorders could be observed in most western countries, among which Alzheimer's disease (AD) is one of the most challenging. BACE1 could be seen as an attractive target to develop disease-modifying compounds, and in this context, a new series of hybrid molecules was designed and synthesized, based on a previously identified multitarget lead compound. In particular, the amino side chain was appropriately modified to fit BACE1 as additional target. In vitro testing results pointed out compound 8 (IC50=2.49±0.08 μM), bearing the bulky bis(4-fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor of the series.

Keywords: AChE; Alzheimer’s disease; BACE1; Drug discovery; Indanone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry*
Acetylcholinesterase / metabolism
Amines / chemistry
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Binding Sites
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry*
Cholinesterase Inhibitors / metabolism
Drug Design
Humans
Indans / chemical synthesis
Indans / chemistry*
Indans / metabolism
Molecular Docking Simulation
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / metabolism
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Amines
Cholinesterase Inhibitors
Indans
Protease Inhibitors
indacrinone
Acetylcholinesterase
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human