Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies

Irene Sola, Ester Aso, Daniela Frattini, Irene López-González, Alba Espargaró, Raimon Sabaté, Ornella Di Pietro, F. Javier Luque, M. Victòria Clos, Isidro Ferrer, Diego Muñoz-Torrero

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33 Citations (Scopus)

Abstract

© 2015 American Chemical Society. We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.
Original languageEnglish
Pages (from-to)6018-6032
JournalJournal of Medicinal Chemistry
Volume58
DOIs
Publication statusPublished - 16 Jul 2015

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    Sola, I., Aso, E., Frattini, D., López-González, I., Espargaró, A., Sabaté, R., Di Pietro, O., Luque, F. J., Clos, M. V., Ferrer, I., & Muñoz-Torrero, D. (2015). Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies. Journal of Medicinal Chemistry, 58, 6018-6032. https://doi.org/10.1021/acs.jmedchem.5b00624