A prodrug of a 2,6-disubstituted 4-(2-arylethenyl)phenol is a selective and orally active 5-lipoxygenase inhibitor.
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.
Department of Biochemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
P R
PR
Farina
A G
AG
Graham
C A
CA
Homon
E S
ES
Lazer
S E
SE
Hattox
P S
PS
Riska
R H
RH
Gundel
C D
CD
Wegner
D000818:Animals; D000941:Antigens; D001682:Biological Availability; D000001:Calcimycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D010636:Phenols / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012453:Saimiri; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D000941:Antigens; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D011355:Prodrugs; D013189:SRS-A; D013876:Thiophenes; C074214:2,6-dimethyl-4-(2-(2-thienyl)ethenyl)phenol; C081300:BI-L 357; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2