ONO-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions.
ONO-4057(5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]valeric acid), an orally active leukotriene B4(LTB4) antagonist, displaced the binding of [3H] LTB4 to the LTB4 receptor in human neutrophil (Ki = 3.7 +/- 0.9 nM). ONO-4057 inhibited the LTB4-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC50) = 0.7 +/- 0.3 microM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB4 (IC50 = 3.0 +/- 0.1, 0.9 +/- 0.1 and 1.6 +/- 0.1 microM) without showing any agonist activity at concentration up to 30 microM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30 microM. In the in vivo study, ONO-4057 given orally, prevented LTB4-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED50) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB4 antagonist and may be a potential candidate for the treatment of various inflammatory diseases.
Kishikawa
K
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Tateishi
N
N
Maruyama
T
T
Seo
R
R
Toda
M
M
Miyamoto
T
T
D000818:Animals; D002118:Calcium / Q000097:blood; D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009503:Neutropenia; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D010666:Phenylpropionates / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000378:metabolism; D018102:Receptors, Leukotriene B4; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D010666:Phenylpropionates; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C067523:ONO-LB 457; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium