A prodrug of a 2,6-disubstituted 4-(2-arylethenyl)phenol is a selective and orally active 5-lipoxygenase inhibitor

PR Farina, AG Graham, CA Homon, ES Lazer, SE Hattox, PS Riska, RH Gundel and CD Wegner

Department of Biochemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

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.

Volume 265, Issue 2, pp. 483-489, 05/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics