Discovery and Optimization of 4‑(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)­transcyclohexane­carboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)­transcyclohexane­carboxylic acid. Although compound 2 produces emesis in humans when given as a single dose,...

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Published inJournal of medicinal chemistry Vol. 58; no. 17; pp. 6747 - 6752
Main Authors Press, Neil J., Taylor, Roger J., Fullerton, Joseph D., Tranter, Pamela, McCarthy, Clive, Keller, Thomas H., Arnold, Nicola, Beer, David, Brown, Lyndon, Cheung, Robert, Christie, Julie, Denholm, Alastair, Haberthuer, Sandra, Hatto, Julia D. I., Keenan, Mark, Mercer, Mark K., Oakman, Helen, Sahri, Helene, Tuffnell, Andrew R., Tweed, Morris, Trifilieff, Alexandre
Format Journal Article
LanguageEnglish
Published American Chemical Society 10.09.2015
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Summary:Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)­transcyclohexane­carboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00902