Interspecies in vitro metabolism of the phosphodiesterase-4 (PDE4) inhibitor L-454,560.

Abstract

L-454,560 is a potent phosphodiesterase 4 (PDE4) inhibitor which was identified as a development candidate for the treatment of asthma and chronic obstructive pulmonary disease (COPD). As part of the discovery of this compound, interspecies in vitro metabolism data was generated using liver microsomes and hepatocytes in order to understand the metabolic fate of the compound. In microsomes, metabolism of the 3-methyl-1,2,4-oxadiazole ring was the predominant pathway observed, including ring cleavage. In rat hepatocytes, hydroxylation of the methyl group on the oxadiazole ring and double-bond isomerization were the most abundant metabolites observed. No major species differences were found in terms of microsomal metabolite profiles. The use of LC with UV and MS detection is highlighted, as well as information from tandem mass spectrometry and NMR.

• Authors: Kevin P Bateman, Laird Trimble, Nathalie Chauret, Jose Silva, Stephen Day, Dwight Macdonald, Daniel Dube, Michel Gallant, Anthony Mastracchio, Helene Perrier, Yves Girard, Deborah Nicoll-Griffith
• Journal: Journal of mass spectrometry : JMS (J Mass Spectrom) Vol. 41 Issue 6 Pg. 771-80 (Jun 2006) ISSN: 1076-5174 [Print] England
• PMID: 16705670 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright (c) 2006 John Wiley & Sons, Ltd.

Chemical References

• L-454,560
• Quinolines
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors)
• Animals
• Chromatography, Liquid (methods)
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Dogs
• Hepatocytes (metabolism)
• Humans
• Macaca mulatta
• Mass Spectrometry (methods)
• Mice
• Microsomes, Liver (metabolism)
• Quinolines (pharmacokinetics)
• Rats
• Saimiri
• Species Specificity
• Spectrophotometry, Ultraviolet (methods)