The peptidoleukotrienes and
leukotriene B4, formed from
arachidonic acid through the action of
5-lipoxygenase (5-LO), exert a spectrum of
biological effects. It has been proposed that potent and selective 5-LO inhibitors will be effective
therapy in diseases in which the peptidoleukotrienes and
leukotriene B4 have been implicated, such as
asthma and
arthritis. The novel compound (S)-N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzyofuranyl )urea (
SB 202235) was evaluated as a selective inhibitor of 5-LO in a cell-free system as well as in various cellular assays. In addition, the potential therapeutic value of
SB 202235 was assessed in preclinical models of allergic
asthma. The activity of the 5-LO
enzyme isolated from rat basophilic leukemia-1 cells was inhibited by
SB 202235 in a concentration-dependent manner with an IC50 value of 1.9 microM. Consistent with its ability to inhibit 5-LO,
SB 202235 inhibited the production of
leukotriene B4 by human monocytes and in human whole blood (IC50 values of 1.5 microM and 1.1 microM, respectively). The selectivity of
SB 202235 was confirmed by its lack of effect against several other
enzymes and receptors.
SB 202235 potently and effectively inhibited the contraction produced by a single concentration of
ovalbumin in guinea pig trachea (IC50 = 20 microM) and of
anti-IgE in human bronchus (IC50 = 2 microM).
SB 202235 (3-30 microM) also inhibited the contraction of guinea pig trachea in response to increasing concentration of
ovalbumin. When administered orally (30 mg/kg) to conscious guinea pigs,
SB 202235 attenuated
antigen-induced broncho-constriction and the subsequent eosinophil influx.(ABSTRACT TRUNCATED AT 250 WORDS)