A prodrug of a 2,6-disubstituted 4-(2-arylethenyl)phenol is a selective and orally active 5-lipoxygenase inhibitor.
J Pharmacol Exp Ther
; 265(2): 483-9, 1993 May.
Article
em En
| MEDLINE
| ID: mdl-8388452
ABSTRACT
BI-L-226, a 2,6-disubstituted 4-(2-arylethenyl)phenol, is a potent and selective 5-lipoxygenase inhibitor which shows excellent inhibition of antigen-induced leukotriene generation in the lung of cynomolgus monkeys by aerosol administration, although little activity has been observed by the p.o. route. The facile synthesis of the succinate ester BI-L-357, however, results in a prodrug which has p.o. activity between 10 to 30 mg/kg in an ex vivo whole blood model of leukotriene B4 generation in both squirrel and cynomolgus monkeys. In addition, the prodrug is effective in inhibiting pulmonary leukotriene C4 production in antigen-challenged cynomolgus monkeys in the same dose range. Plasma levels of the parent compound in the monkey after p.o. administration of 30 mg/kg are 25-fold higher than the IC50 needed for in vitro inhibition of leukotriene B4 in whole blood. Absolute bioavailability of the parent compound was 50%. The prodrug concept therefore extends the potential of this class of compounds to inflammation sites mediated by 5-lipoxygenase not readily treated by topical administration.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenóis
/
Tiofenos
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Pró-Fármacos
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Inibidores de Lipoxigenase
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Pharmacol Exp Ther
Ano de publicação:
1993
Tipo de documento:
Article