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

Press, Neil and Taylor, Roger and Fullerton, Joe and Tranter, Pamela and Mccarthy, Clive and Keller, Thomas and Arnold, Nicola and Brown, Lyndon and Cheung, Robert and Christie, Julie and Denholm, Alastair and Haberthuer, Sandra and Keenan, Mark and Hatto, Julia and Mercer, Mark and Oakman, Helen and Sahri, Helene and Trifilieff, Alexandre and Tuffnell, Andrew and Tweed, Morris and Wagner, Beatrix and Beer, David and Tyler, John and Fozard, John R. (2012) Solubility-Driven Optimisation of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate. Journal of medicinal chemistry, 55 (17). pp. 7472-7479. ISSN 0022-2623


The solubility-driven optimisation 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 synthesised. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

Item Type: Article
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Additional Information: All compounds previously disclosed in patent applications or oral presentations
Keywords: Phosphodiesterase-4; Asthma; COPD; Anti- inflammatory, solubility-driven optimisation
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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