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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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 0.1 mg/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.

References and notes (17)

  • M.J. Curtis

    J. Pharmacol. Toxicol.

    (2004)
  • H. Guthrie et al.

    J. Biomol. Screen.

    (2005)
  • Q. Wang et al.

    Int. J. Pharm.

    (2005)
  • Y. Zhang et al.

    Clin. Pharmacokinet.

    (2001)
  • C. Virginio et al.

    Eur. J. Pharmacol.

    (2002)
  • J. Skidmore

    Bioorg. Med. Chem. Lett.

    (2012)
  • S.G. Summerfield et al.

    Pharmacol. Exp. Ther.

    (2006)
There are more references available in the full text version of this article.

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Present address: The University Chemical Laboratory, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.

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Present address: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

Present address: Neurosciences division, Johnson and Johnson PRF, Turnhoutseweg 30, B2340 Beerse, Belgium.

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