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 |
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| Authors: | Skidmore John Atcha Zeenat Boucherat Emmanuelle Castelletti Laura Chen Deborah W Coppo Frank T Cutler Leanne Dunsdon Rachel M Heath Bronagh M Hutchings Rio Hurst David N Javed Sahar Martin Samuel Maskell Emma S L Norton David Pemberton Darrel J Redshaw Sally Rutter Richard Sehmi Sanjeet S Scoccitti Tiziana Temple Hannah E Theobald Pam Ward Robert W Wilson David M |
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| Institution: | Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. js930@cam.ac.uk |
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| Abstract: | 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. |
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