John Skidmore,
Zeenat Atcha,
Emmanuelle Boucherat,
Laura Castelletti,
Deborah W Chen,
Frank T Coppo,
Leanne Cutler,
Rachel M Dunsdon,
Bronagh M Heath,
Rio Hutchings, [......],
David Norton,
Darrel J Pemberton,
Sally Redshaw,
Richard Rutter,
Sanjeet S Sehmi, Tiziana Scoccitti,
Hannah E Temple,
Pam Theobald,
Robert W Ward,
David M Wilson
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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.
Bioorganic & medicinal chemistry letters 03/2012; 22(10):3531-4. · 2.65 Impact Factor