title: 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.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Pointe Claire-Dorval, Kirkland, Quebec, Canada. Kevin.Bateman@merck.com
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bateman
authors.forename: Laird
authors.initials: L
authors.lastname: Trimble
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Jose
authors.initials: J
authors.lastname: Silva
authors.forename: Stephen
authors.initials: S
authors.lastname: Day
authors.forename: Dwight
authors.initials: D
authors.lastname: Macdonald
authors.forename: Daniel
authors.initials: D
authors.lastname: Dube
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Helene
authors.initials: H
authors.lastname: Perrier
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
authors.forename: Deborah
authors.initials: D
authors.lastname: Nicoll-Griffith
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D012453:Saimiri; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet / Q000379:methods
chemical_list: C507187:L-454,560; D011804:Quinolines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4