Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.
Lewy body dementia
multitarget-directed ligands (MTDLs)
neflamapimod
p38α-MAPK
propargylamine
Journal
Archiv der Pharmazie
ISSN: 1521-4184
Titre abrégé: Arch Pharm (Weinheim)
Pays: Germany
ID NLM: 0330167
Informations de publication
Date de publication:
27 Feb 2024
27 Feb 2024
Historique:
revised:
03
02
2024
received:
21
09
2023
accepted:
06
02
2024
medline:
27
2
2024
pubmed:
27
2
2024
entrez:
27
2
2024
Statut:
aheadofprint
Résumé
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
Identifiants
pubmed: 38412454
doi: 10.1002/ardp.202300525
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2300525Subventions
Organisme : CSC - Finland
Organisme : FEDER/COMPETE
Organisme : Foundation for Science and Technology
ID : UIDB/00081/2020 (CIQUP)
Organisme : Foundation for Science and Technology
ID : LA/P/0056/2020 (IMS)
Organisme : GrantRFO 2021 - University of Bologna
Organisme : TüCAD2 and CMIF are funded by the Federal Ministry of Education and Research (BMBF) and the Baden-Württemberg Ministry of Science as part of the Excellence Strategy of the German Federal and State Governments
ID : 390838134
Informations de copyright
© 2024 Deutsche Pharmazeutische Gesellschaft.
Références
World Alzheimer Reports. 2023. https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/#:~:text=There%20are%20over%2055%20million,will%20be%20in%20developing%20countries
S. Y. Chiu, D. Bowers, M. J. Armstrong, Neurotherapeutics 2022, 19, 55.
E. King, J. T. O'Brien, P. Donaghy, C. Morris, N. Barnett, K. Olsen, C. Martin-Ruiz, J.-P. Taylor, A. J. Thomas, J. Neurol. Neurosurg. Psychiatry 2018, 89, 339.
A. Surendranathan, L. Su, E. Mak, L. Passamonti, Y. T. Hong, R. Arnold, P. Vázquez Rodríguez, W. R. Bevan-Jones, S. A. E. Brain, T. D. Fryer, F. I. Aigbirhio, J. B. Rowe, J. T. O'Brien, Brain 2018, 141, 3415.
E. D. Pope, L. Cordes, J. Shi, Z. Mari, B. Decourt, M. N. Sabbagh, Expert Opin. Invest. Drugs 2021, 30, 603.
J. P. Duffy, E. M. Harrington, F. G. Salituro, J. E. Cochran, J. Green, H. Gao, G. W. Bemis, G. Evindar, V. P. Galullo, P. J. Ford, U. A. Germann, K. P. Wilson, S. F. Bellon, G. Chen, P. Taslimi, P. Jones, C. Huang, S. Pazhanisamy, Y. M. Wang, M. A. Murcko, M. S. S. Su, ACS Med. Chem. Lett. 2011, 2, 758.
U. A. Germann, J. J. Alam, Int. J. Mol. Sci. 2020, 21, 5485.
N. D. Prins, J. E. Harrison, H. M. Chu, K. Blackburn, J. J. Alam, P. Scheltens, Alzheimer's Res. Ther. 2021, 13, 106.
Y. Jiang, J. J. Alam, S. N. Gomperts, P. Maruff, A. W. Lemstra, U. A. Germann, P. H. Stavrides, S. Darji, S. Malampati, J. Peddy, C. Bleiwas, M. Pawlik, A. Pensalfini, D.-S. Yang, S. Subbanna, B. S. Basavarajappa, J. F. Smiley, A. Gardner, K. Blackburn, H.-M. Chu, N. D. Prins, C. E. Teunissen, J. E. Harrison, P. Scheltens, R. A. Nixon, Nat. Commun. 2022, 13, 5308.
R. R. Ramsay, A. Albreht, J. Neural Transm. 2018, 125, 1659.
M. do Carmo Carreiras, L. Ismaili, J. Marco-Contelles, Bioorg. Med. Chem. Lett. 2020, 30, 126880.
M. B. H. Youdim, M. Weinstock, Cell. Mol. Neurobiol. 2001, 21, 555.
A. Chimagomedova, O. Levin, M. Anikina, I. Ayzenberg, Mov. Disord. 2018, 33(suppl 2), S26.
A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre, J. Med. Chem. 2008, 51, 347.
C. Albertini, A. Salerno, P. de Sena Murteira Pinheiro, M. L. Bolognesi, Med. Res. Rev. 2020, 41, 2606. https://doi.org/10.1002/med.21699
V. Ivasiv, C. Albertini, A. E. Gonçalves, M. Rossi, M. L. Bolognesi, Curr. Top. Med. Chem. 2019, 19, 1694.
M. Decker, Design of Hybrid Molecules for Drug Development, Elsevier, Amsterdam, Netherlands 2017.
A. Carneiro, E. Uriarte, F. Borges, M. J. Matos, Future Med. Chem. 2023, 15, 211.
F. T. Zindo, J. Joubert, S. F. Malan, Future Med. Chem. 2015, 7, 609.
F. Mesiti, D. Chavarria, A. Gaspar, S. Alcaro, F. Borges, Eur. J. Med. Chem. 2019, 181, 111572.
C. Albertini, A. Salerno, S. Atzeni, E. Uliassi, F. Massenzio, A. Maruca, R. Rocca, M. Mecava, F. S. G. Silva, D. Mena, P. Valente, A. I. Duarte, D. Chavarria, M. Bissaro, S. Moro, S. Federico, G. Spalluto, O. Soukup, F. Borges, S. Alcaro, B. Monti, P. J. Oliveira, J. C. Menéndez, M. L. Bolognesi, ACS Chem. Neurosci. 2022, 13, 2252.
F. Salituro, G. Bemis, G. Evindar (Vertex Pharmaceuticals Inc.), CA2403828A1, 2001.
P. Traxler, P. Furet, Pharmacol. Ther. 1999, 82, 195.
C. Binda, M. Aldeco, W. J. Geldenhuys, M. Tortorici, A. Mattevi, D. E. Edmondson, ACS Med. Chem. Lett. 2011, 3, 39.
P. A. Iglesias González, M. A. Conde, V. González-Pardo, R. M. Uranga, G. A. Salvador, Toxicol. In Vitro 2019, 60, 400.
X. Lu, J. S. Kim-Han, S. Harmon, S. E. Sakiyama-Elbert, K. L. O'Malley, Mol. Neurodegener. 2014, 9, 17.
T. M. Miller, E. M. Johnson Jr., J. Neurosci. 1996, 16, 7487.
K. N. Green, L. M. Billings, B. Roozendaal, J. L. McGaugh, F. M. LaFerla, J. Neurosci. 2006, 26, 9047.
J. Burtscher, J.-C. Copin, J. Rodrigues, S. T. Kumar, A. Chiki, I. Guillot de Suduiraut, C. Sandi, H. A. Lashuel, Neurobiol. Aging 2019, 83, 11.
W. Suwanjang, A. Y. Abramov, P. Govitrapong, B. Chetsawang, J. Steroid. Biochem. Mol. Biol. 2013, 138, 116.
S. Johnson, S. Tazik, D. Lu, C. Johnson, M. B. H. Youdim, J. Wang, G. Rajkowska, X. M. Ou, Front. Neurosci. 2010, 4, 180.
A. Surendranathan, J. B. Rowe, J. T. O'Brien, Parkinsonism Relat. Disord. 2015, 21, 1398.
J. J. Alam, J. Alzheimers Dis. n.d., 48, 219-227.
D. Trudler, O. Weinreb, S. A. Mandel, M. B. H. Youdim, D. Frenkel, J. Neurochem. 2014, 129, 434.
L. Nieto, A. Mascaraque, F. Miller, F. Glacial, C. Ríos Martínez, M. Kaiser, R. Brun, C. Dardonville, J. Med. Chem. 2011, 54, 485.
B. Poller, H. Gutmann, S. Krähenbühl, B. Weksler, I. Romero, P.-O. Couraud, G. Tuffin, J. Drewe, J. Huwyler, J. Neurochem. 2008, 107, 1358.
C. Abdelnour, M. C. Gonzalez, L. L. Gibson, K. L. Poston, C. G. Ballard, J. L. Cummings, D. Aarsland, Neurol. Ther. 2023, 12, 727.
E. Uliassi, L. E. Peña-Altamira, A. V. Morales, F. Massenzio, S. Petralla, M. Rossi, M. Roberti, L. Martinez Gonzalez, A. Martinez, B. Monti, M. L. Bolognesi, ACS Chem. Neurosci. 2019, 10, 279.
B. B. Weksler, E. A. Subileau, N. Perrière, P. Charneau, K. Holloway, M. Leveque, H. Tricoire-Leignel, A. Nicotra, S. Bourdoulous, P. Turowski, D. K. Male, F. Roux, J. Greenwood, I. A. Romero, P. O. Couraud, FASEB J. 2005, 19, 1872.
C. Riganti, I. C. Salaroglio, M. L. Pinzòn-Daza, V. Caldera, I. Campia, J. Kopecka, M. Mellai, L. Annovazzi, P.-O. Couraud, A. Bosia, D. Ghigo, D. Schiffer, Cell. Mol. Life Sci. 2014, 71, 499.
C. Förster, M. Burek, I. A. Romero, B. Weksler, P.-O. Couraud, D. Drenckhahn, J. Physiol. 2008, 586, 1937.
R. Rane, R. Shelar, Y. Shinde, S. Lad, S. Desai, M. Vartak, Int. J. Pharm. Res. Health Sci. 2018, 6, 2160.