作者: Cañada, F Javier ; Martinez, Ana ; Pérez, Daniel I ; Pedersoli-Mantoani, Susimaire ; Canales, Angeles ; Sebastian-Pérez, Victor ; Roca, Carlos ; Campillo, Nuria E ; Carvalho, Ivone ; Martínez-Gonzalez, Loreto ; Perez, Concepción ; Chierrito, Talita P C

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE.

2008-01-01·Neurodegenerative Diseases4区 · 医学

Potent β-Amyloid Modulators

4区 · 医学

Review

作者: Munoz, P. ; Medina, M. ; Garcia, P. ; Rubio, L. ; Valenzuela, R. ; Delgado, E. ; Usan, P. ; Martinez, A. ; Garcia-Palomero, E. ; De Austria, C.

Currently, the potential to interfere with the pathology of β-amyloid targeting a well-known drugable enzyme, the acetylcholinesterase (AChE), is opened. Peripheral or dual binding site inhibitors of AChE may simultaneously alleviate the cognitive and behavioral deficits in Alzheimer’s disease (AD) patients and, more importantly, act as disease-modifying agents delaying amyloid plaque formation. As part of a rational drug design program directed to find dual binding site AChE inhibitors, several families of compounds have been synthesized as potent AChE inhibitors. From these series, several drug candidates were selected based on their potent and selective inhibition of AChE (subnanomolar activity) and their interference with the β-amyloid aggregation in vitro (IC<sub>50</sub> in the low micromolar range). First in vivo data confirm our initial hypothesis. Oral treatment with NP-61 for 3 months is able to reverse the cognitive impairment (Morris water maze test) and to reduce plaque load in the brains of human amyloid precursor protein transgenic mice (Swedish mutation). These results suggest that NP-61, a potent β-amyloid modulator, is able to reverse the AD-like neurodegenerative phenotype in transgenic mice, indicating a promising disease-modifying agent for clinical application.

100 项与 NP-0361 相关的药物交易

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