Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology.
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Chaudhaery SS, Roy KK, Shakya N, Saxena G, Sammi SR, Nazir A, Nath C, Saxena AK
Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology.
J Med Chem. 2010 Sep 9;53(17):6490-505. doi: 10.1021/jm100573q.
- PubMed ID
- 20684567 [ View in PubMed]
- Abstract
A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Donepezil Acetylcholinesterase IC 50 (nM) 90 N/A N/A Details Phenserine Acetylcholinesterase IC 50 (nM) 22.1 N/A N/A Details Physostigmine Acetylcholinesterase IC 50 (nM) 56.7 N/A N/A Details Rivastigmine Acetylcholinesterase IC 50 (nM) 4150 N/A N/A Details Tacrine Acetylcholinesterase IC 50 (nM) 800 N/A N/A Details