The discovery of 2-fluoro-N-(3-fluoro-4-(5-((4-morpholinobutyl)amino)-1,3,4-oxadiazol-2-yl)phenyl)benzamide, a full agonist of the alpha-7 nicotinic acetylcholine receptor showing efficacy in the novel object recognition model of cognition enhancement.

Autor: Skidmore J; Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. js930@cam.ac.uk, Atcha Z, Boucherat E, Castelletti L, Chen DW, Coppo FT, Cutler L, Dunsdon RM, Heath BM, Hutchings R, Hurst DN, Javed S, Martin S, Maskell ES, Norton D, Pemberton DJ, Redshaw S, Rutter R, Sehmi SS, Scoccitti T, Temple HE, Theobald P, Ward RW, Wilson DM
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 May 15; Vol. 22 (10), pp. 3531-4. Date of Electronic Publication: 2012 Mar 21.
DOI: 10.1016/j.bmcl.2012.03.062
Abstrakt: A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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