Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors
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)
- et al.
Bioorg. Med. Chem. Lett.
(2011) - et al.
J. Pharmacol. Toxicol. Methods
(2008) Lancet
(2005)- et al.
Immunopharmacology
(2000) - et al.
Bioorg. Med. Chem. Lett.
(2010) - et al.
Bioorg. Med. Chem. Lett.
(2011) - et al.
Bioorg. Med. Chem. Lett.
(2006) - et al.
Bioorg. Med. Chem. Lett.
(2011) - et al.
Bioorg. Med. Chem. Lett.
(2012) - et al.
Bioorg. Med. Chem. Lett.
(2010)
Bioorg. Med. Chem. Lett.
Pulm. Pharmacol. Ther.
Am. Rev. Respir. Dis.
Am. J. Respir. Cell Mol. Biol.
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