OPTIMIZATION OF THE POTENCY AND DURATION OF ACTION OF N-HYDROXYUREA 5-LIPOXYGENASE INHIBITORS

An in vitro glucuronidation assay and several biochemical assays were utilized to discover potent new N-hydroxyurea-containing 5-lipoxygenas e inhibitors with long durations of action. The best of these, A-78773 , is a racemic mixture of two enantiomers. These enantiomers were puri fied and the R(+)-enantiomer A-79175 was found to be superior to the S (-)-enantiomer with respect to in vitro metabolism and duration of act ion in the monkey. A-79175 was a potent selective inhibitor of 5-hydro xyeicosatetraenoic acid formation in rat basophilic leukemic homogenat es (IC50 = 54 nM) and of calcium ionophore-induced leukotriene B-4 (LT B(4)) formation in purified human polymorphonuclear leukocytes (IC50 = 25 nM) and human whole blood (IC50 = 80 nM). The compound inhibited L T formation in the rat with oral ED(50)s of 1 to 2 mg/kg. It also was a potent inhibitor of edema and inflammatory cell influx in rats and m ice. A-79175 was resistant to glucuronidation and had an elimination h alf-life of nearly 9 hr in cynomolgus monkeys. A-79175 inhibited ex vi vo LTB(4) formation by monkeys for extended periods. A single 0.5-mg/k g oral dose gave > 50% inhibition of calcium ionophore-induced LTB(4) formation ex vivo for 12 hr. A good correlation was found between the elimination half-life for A-78773 and its enantiomers in cynomolgus mo nkeys and humans. These data indicate that A-79175 is a promising long -acting agent that should be useful to delineate the importance of LTs in animal and human studies.