Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies
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- 作者：Irene Sola ; Ester Aso ; Daniela Frattini ; Irene L贸pez-Gonz谩lez ; Alba Espargar贸 ; Raimon Sabat茅 ; Ornella Di Pietro ; F. Javier Luque ; M. Vict貌ria Clos ; Isidro Ferrer ; Diego Mu帽oz-Torrero
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：58
- 期：15
- 页码：6018-6032
- 全文大小：560K
- ISSN：1520-4804
文摘
We have synthesized a series of heptamethylene-linked levetiracetam鈥揾uprine and levetiracetam鈥?6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as 尾-amyloid (A尾)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer鈥檚 disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent A尾42 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鈥揾uprine 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.