Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Autor: Albertini C; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Petralla S; Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany., Massenzio F; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Monti B; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Rizzardi N; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Bergamini C; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Uliassi E; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Borges F; CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Chavarria D; CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Fricker G; Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany., Goettert M; Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany., Kronenberger T; Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Gehringer M; Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany., Laufer S; Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany., Bolognesi ML; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Jun; Vol. 357 (6), pp. e2300525. Date of Electronic Publication: 2024 Feb 27.
DOI: 10.1002/ardp.202300525
Abstrakt: 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 (IC 50  = 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.
(© 2024 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
Externí odkaz: