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)

Autor:	Nicola Arnold, Julie Christie, Sandra Haberthuer, Roger J. Taylor, Alastair Denholm, Mark Keenan, Julia Hatto, Mark Mercer, Lyndon Nigel Brown, Clive Mccarthy, Neil John Press, Helen Oakman, Andrew R. Tuffnell, Morris Tweed, Alexandre Trifilieff, Robert Cheung, Joseph D. Fullerton, Thomas H. Keller, David Beer, Helene Sahri, Pamela Tranter
Rok vydání:	2015
Předmět:	Drug Cyclohexanecarboxylic Acids Vomiting Nausea media_common.quotation_subject Pulmonary disease Pharmacology Pulmonary Disease Chronic Obstructive Structure-Activity Relationship Pharmacokinetics Drug Discovery medicine Animals Humans Structure–activity relationship Dosing Naphthyridines PDE4 Inhibitors media_common COPD Dose-Response Relationship Drug Chemistry medicine.disease Rats Solubility Thermodynamics Molecular Medicine Phosphodiesterase 4 Inhibitors medicine.symptom
Zdroj:	Journal of Medicinal Chemistry. 58:6747-6752
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f1713cba513710940b786b9defedf19 https://doi.org/10.1021/acs.jmedchem.5b00902 Zobrazit plný text záznamu