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Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

2012; American Chemical Society; Volume: 55; Issue: 17 Linguagem: Inglês

10.1021/jm300459a

1520-4804

Neil J. Press, Roger Taylor, Joseph D. Fullerton, Pamela Tranter, Clive McCarthy, Thomas H. Keller, Nicola Arnold, David Beer, Lyndon Brown, Robert Cheung, Julie Christie, Alastair A. Denholm, Sandra Haberthuer, Julia Hatto, Mark Keenan, Mark K. Mercer, Helen Oakman, Helene Sahri, Andrew R. Tuffnell, Morris Tweed, John W. Tyler, Trixie Wagner, John R. Fozard, Alexandre Trifilieff,

Cholinesterase and Neurodegenerative Diseases

The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.