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Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560
Author(s) -
Bateman Kevin P.,
Trimble Laird,
Chauret Nathalie,
Silva Jose,
Day Stephen,
Macdonald Dwight,
Dube Daniel,
Gallant Michel,
Mastracchio Anthony,
Perrier Helene,
Girard Yves,
NicollGriffith Deborah
Publication year - 2006
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.1033
Subject(s) - chemistry , microsome , metabolite , hydroxylation , metabolism , in vitro , biochemistry , tandem mass spectrometry , metabolic pathway , stereochemistry , mass spectrometry , enzyme , chromatography
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.