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Targeting Lewy body dementia with neflamapimod-rasagiline hybrids

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurpos...

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Main Authors: Albertini, Claudia (Author) , Petralla, Sabrina (Author) , Massenzio, Francesca (Author) , Monti, Barbara (Author) , Rizzardi, Nicola (Author) , Bergamini, Christian (Author) , Uliassi, Elisa (Author) , Borges, Fernanda (Author) , Chavarria, Daniel (Author) , Fricker, Gert (Author) , Goettert, Marcia (Author) , Kronenberger, Thales (Author) , Gehringer, Matthias (Author) , Laufer, Stefan (Author) , Bolognesi, Maria L. (Author)
Format: Article (Journal)
Language:English
Published: June 2024
In: Archiv der Pharmazie
Year: 2024, Volume: 357, Issue: 6, Pages: 1-11
ISSN:1521-4184
DOI:10.1002/ardp.202300525
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/ardp.202300525
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ardp.202300525
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Author Notes:Claudia Albertini, Sabrina Petralla, Francesca Massenzio, Barbara Monti, Nicola Rizzardi, Christian Bergamini, Elisa Uliassi, Fernanda Borges, Daniel Chavarria, Gert Fricker, Marcia Goettert, Thales Kronenberger, Matthias Gehringer, Stefan Laufer, Maria L. Bolognesi
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Summary:Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 μM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 μM concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1.
Item Description:Zuerst veröffentlicht: 27. Februar 2024
Gesehen am 25.07.2024
Physical Description:Online Resource
ISSN:1521-4184
DOI:10.1002/ardp.202300525

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