BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease

Federica Prati, Giovanni Bottegoni, Maria Laura Bolognesi, Andrea Cavalli (Lead / Corresponding author)

Research output: Contribution to journalReview article

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Abstract

The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.

Original languageEnglish
Pages (from-to)619-637
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
Early online date27 Jul 2017
DOIs
Publication statusPublished - 8 Feb 2018

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Alzheimer Disease
Drug Discovery
Amyloid
Amyloid beta-Protein Precursor
Pharmaceutical Preparations
Enzymes
Therapeutics

Cite this

Prati, Federica ; Bottegoni, Giovanni ; Bolognesi, Maria Laura ; Cavalli, Andrea. / BACE-1 Inhibitors : From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 3. pp. 619-637.
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abstract = "The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.",
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BACE-1 Inhibitors : From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease. / Prati, Federica; Bottegoni, Giovanni; Bolognesi, Maria Laura; Cavalli, Andrea (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 61, No. 3, 08.02.2018, p. 619-637.

Research output: Contribution to journalReview article

TY - JOUR

T1 - BACE-1 Inhibitors

T2 - From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease

AU - Prati, Federica

AU - Bottegoni, Giovanni

AU - Bolognesi, Maria Laura

AU - Cavalli, Andrea

N1 - We thank the University of Bologna and the Italian Institute of Technology for financial support.

PY - 2018/2/8

Y1 - 2018/2/8

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AB - The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.

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