Aqueous stability of SB 210661: kinetics and primary degradation mechanisms of an N-hydroxyurea-containing 5-lipoxygenase inhibitor.
SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzo furanyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds. Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH > 5 and different degradative pathways at pH < 5. The pathway at pH > 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH < 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.
McLoughlin
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Pharmaceutical Development, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Kearney
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Palepu
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D001572:Benzofurans / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000737:chemistry; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000737:chemistry*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry; D014867:Water
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C111788:SB 210661; D014867:Water; C082739:A 78773; D014508:Urea; C063449:zileuton; D006918:Hydroxyurea