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

• Published in: Journal of mass spectrometry. Vol. 41; no. 6; pp. 771 - 780
• Main Authors: Bateman, Kevin P., Trimble, Laird, Chauret, Nathalie, Silva, Jose, Day, Stephen, Macdonald, Dwight, Dube, Daniel, Gallant, Michel, Mastracchio, Anthony, Perrier, Helene, Girard, Yves, Nicoll-Griffith, Deborah
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-06-2006; Wiley
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Analysis; Animals; Biological and medical sciences; Chromatography, Liquid - methods; Cyclic Nucleotide Phosphodiesterases, Type 4; Dogs; General pharmacology; Hepatocytes - metabolism; Humans; L-454; L‐454,560; Macaca mulatta; Mass Spectrometry - methods; Medical sciences; metabolite identification; Mice; Microsomes, Liver - metabolism; oxadiazole; Pharmacology. Drug treatments; phospodiesterase; Quinolines - pharmacokinetics; Rats; Respiratory system; Saimiri; Species Specificity; Spectrophotometry, Ultraviolet - methods; Chemical analysis; Rat; Sulfone; Metabolite; Liver; Monkey; HPLC chromatography; Esterases; Phosphoric diester hydrolases; Antiasthma agent; Microsome; Hepatocyte; Primates; Oxadiazole derivatives; phospodiesterase; L-454,560; Qualitative analysis; Dog; Human; Fissipedia; Carnivora; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Coupled method; Interspecific comparison; Rodentia; Enzyme inhibitor; Quinoline derivatives; Metabolism; In vitro; Vertebrata; Mammalia; Ultraviolet detector; Mouse; Mass spectrometry MS/MS; oxadiazole; Hydrolases; Benzenic compound; metabolite identification
• ISSN: 1076-5174; 1096-9888
• DOI: 10.1002/jms.1033

L‐454,560 is a potent phospodiesterase 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. Copyright © 2006 John Wiley & Sons, Ltd.