A-78773

As in vitro glucuronidation assay and several biochemical assays were utilized to discover potent new N-hydroxyurea-containing 5-lipoxygenase inhibitors with long durations of action. The best of these, A-78773, is a racemic mixture of two enantiomers. These enantiomers were purified and the R(+)-enantiomer A-79175 was found to be superior to the S(-)-enantiomer with respect to in vitro metabolism and duration of action in the monkey. A-79175 was a potent selective inhibitor of 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemic homogenates (IC50 = 54 nM) and of calcium ionophore-induced leukotriene B4 (LTB4) formation in purified human polymorphonuclear leukocytes (IC50 = 25 nM) and human whole blood (IC50 = 80 nM). The compound inhibited LT formation in the rat with oral ED50s of 1 to 2 mg/kg. It also was a potent inhibitor of edema and inflammatory cell influx in rats and mice. A-79175 was resistant to glucuronidation and had an elimination half-life of nearly 9 hr in cynomolgus monkeys. A-79175 inhibited ex vivo LTB4 formation by monkeys for extended periods. A single 0.5-mg/kg oral dose gave > 50% inhibition of calcium ionophore-induced LTB4 formation ex vivo for 12 hr. A good correlation was found between the elimination half-life for A-78773 and its enantiomers in cynomolgus monkeys 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.

Leukotrienes (LTs) are considered to be involved in the genesis of the symptoms which characterize allergic rhinitis.Elevated levels of immunoreactive leukotriene (LT)C₄ and LTD₄ have been reported in nasal lavage fluid from patients with perennial and seasonal allergic rhinitis.In acute provoked disease, nasal lavage studies reveal an increase in luminal levels of LTB₄, LTC₄, LTD₄ and LTE₄ within 10 min of nasal allergen challenge and further increments in both LTB₄ and LTC₄ are reported during the late-phase nasal response to allergen challenge.These increments are allergen directed, as no changes in LTC₄ levels in nasal lavage can be identified following nasal challenge with saline, methacholine, or bradykinin.The relevance of these mediator changes to symptom generation has been suggested from nasal insufflation studies.Both LTC₄ and LTD₄ can induce an immediate and sustained increase in nasal airway resistance in the absence of any effect on nasal itch or sneezing.These findings indicate a vascular, rather than a neural effect of topically administered LT within the nose.Consistent with this, in addition to its effects on the state of engorgement of the venous sinusoids, changes in nasal mucosal blood flow are also described with LTD₄.To confirm the relevance of these nasal studies involving LTs to allergic rhinitis, we have investigated the influence of a novel N-hydroxyurea 5-lipoxygenase inhibitor, N-[3-[5-(4-fluorophenoxy)-2-furanyl]-1-methyl-2-propynyl]-N-hydroxyurea (A-78773), on the acute nasal response to allergen challenge.Findings identify the efficacy within the nose of 5-lipoxygenase inhibition with A-78773, when administered as a single 400-mg dose, and indicate the relevance of LT release to allergen-induced nasal obstruction, rhinorrhea, and plasma protein leakage.