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Your search keyword '"Oakman H"' showing total 2 results
Start Over Author "Oakman H" Journal journal of medicinal chemistry
2 results on '"Oakman H"'

1. 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).

Author

Press NJ, Taylor RJ, Fullerton JD, Tranter P, McCarthy C, Keller TH, Arnold N, Beer D, Brown L, Cheung R, Christie J, Denholm A, Haberthuer S, Hatto JD, Keenan M, Mercer MK, Oakman H, Sahri H, Tuffnell AR, Tweed M, and Trifilieff A

Subjects
Animals, Cyclohexanecarboxylic Acids pharmacokinetics, Cyclohexanecarboxylic Acids pharmacology, Dose-Response Relationship, Drug, Humans, Naphthyridines pharmacokinetics, Naphthyridines pharmacology, Nausea chemically induced, Phosphodiesterase 4 Inhibitors pharmacokinetics, Phosphodiesterase 4 Inhibitors pharmacology, Rats, Solubility, Structure-Activity Relationship, Thermodynamics, Vomiting chemically induced, Cyclohexanecarboxylic Acids chemistry, Naphthyridines chemistry, Phosphodiesterase 4 Inhibitors chemistry, Pulmonary Disease, Chronic Obstructive drug therapy
Abstract

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.

Published
2015
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2. Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate.

Author

Press NJ, Taylor RJ, Fullerton JD, Tranter P, McCarthy C, Keller TH, Arnold N, Beer D, Brown L, Cheung R, Christie J, Denholm A, Haberthuer S, Hatto JD, Keenan M, Mercer MK, Oakman H, Sahri H, Tuffnell AR, Tweed M, Tyler JW, Wagner T, Fozard JR, and Trifilieff A

Subjects
Animals, Cells, Cultured, Disease Models, Animal, Drug Design, Drug Evaluation, Preclinical, Humans, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Phosphodiesterase 4 Inhibitors pharmacokinetics, Phosphodiesterase 4 Inhibitors therapeutic use, Rats, Solubility, Vomiting drug therapy, Phosphodiesterase 4 Inhibitors chemistry, Phosphodiesterase 4 Inhibitors pharmacology
Abstract

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.

Published
2012
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