Pharmacological characterization of SB 202235, a potent and selective 5-lipoxygenase inhibitor: effects in models of allergic asthma.
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)
Chabot-Fletcher
M C
MC
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Underwood
D C
DC
Breton
J J
JJ
Adams
J L
JL
Kagey-Sobotka
A
A
Griswold
D E
DE
Marshall
L A
LA
Sarau
H M
HM
Winkler
J D
JD
Hay
D W
DW
D000818:Animals; D000941:Antigens / Q000502:physiology; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D016084:Bronchoconstriction / Q000187:drug effects; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000941:Antigens; D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C094196:N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzofuranyl)urea; D007975:Leukotriene B4; D014508:Urea