Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 67, Issue -, Pages 64-74Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.06.021
Keywords
hAChE; hBuChE; Dual AChE inhibitors; 6-Chloro-pyridonepezils; In vitro blood brain barrier; Molecular modeling; ADME; Alzheimer's disease
Categories
Funding
- CSIC [PIE-201280E074]
- MICINN [SAF2009-07271, SAF2012-33304]
- COST EU [CM1103 Action]
- Spanish Ministry of Economy and Competitiveness [SAF2012-31035]
- Fundacion de Investigacion Medica Mutua Madrilena Automovilistica [AP103952012]
Ask authors/readers for more resources
6-Chloro-pyridonepezils are chloropyridine donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1-8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine3,5-dicarbonitrile (14)1 with suitable 2-(1-benzylpiperidin-4-yDalkylamines (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 +/- 0.08 mu M). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 mu M range. Particularly, 6-chloro-pyridonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1-8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy. (C) 2013 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available