Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors

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Abstract

A novel series of formoterol–phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50 = 1.05 nM, pEC50 = 9.0) and potent PDE4B2 inhibitory activities (IC50 = 0.092 μM).

Graphical abstract

A novel series of formoterol–phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50 = 1.05 nM, pEC50 = 9.0) and potent PDE4B2 inhibitory activities (IC50 = 0.092 μM).

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Acknowledgments

We thank the State Key Laboratory of Respiratory Diseases (2007DA-80154F1110), National Natural Science Foundation of China (No. 21302235), Ph.D. Programs Foundation of Ministry of Education of China (20120171120045), and Distinguished Young Talents in Higher Education of Guangdong (2012LYM_003) for financial support of this study.

References and notes (28)

  • M. Prat et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • S. Summerhill et al.

    J. Pharmacol. Toxicol. Methods

    (2008)
  • B.J. Lipworth

    Lancet

    (2005)
  • J.E. Souness et al.

    Immunopharmacology

    (2000)
  • D. Beattie et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • A.D. Hughes et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • L. Provins et al.

    Bioorg. Med. Chem. Lett.

    (2006)
  • L.H. Jones et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • W.-J. Shan et al.

    Bioorg. Med. Chem. Lett.

    (2012)
  • M.A. Soriano-Ursúa et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • W.J. Shan et al.

    Bioorg. Med. Chem. Lett.

    (2012)
  • D.A. Handley et al.

    Pulm. Pharmacol. Ther.

    (2002)
  • N. Carroll et al.

    Am. Rev. Respir. Dis.

    (1993)
  • M. John et al.

    Am. J. Respir. Cell Mol. Biol.

    (1998)
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