Kishikawa K, Tateishi N, Maruyama T, Seo R, Toda M, Miyamoto T
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Prostaglandins. 1992 Oct;44(4):261-75. doi: 10.1016/0090-6980(92)90002-b.
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.
ONO - 4057（5 - [2 - （2 - 羧乙基） - 3 - [6 - （4 - 甲氧基苯基） - 5E - 己烯基]氧基苯氧基]戊酸）是一种口服活性白三烯B4（LTB4）拮抗剂，它能取代[3H]LTB4与人中性粒细胞中LTB4受体的结合（Ki = 3.7 ± 0.9 nM）。ONO - 4057抑制LTB4诱导的胞质游离钙升高（引起50%抑制的浓度（IC50） = 0.7 ± 0.3 μM），并抑制LTB4诱导的人中性粒细胞聚集、趋化或脱颗粒（IC50 = 3.0 ± 0.1、0.9 ± 0.1和1.6 ± 0.1 μM），在浓度高达30 μM时未表现出任何激动剂活性。在浓度高达30 μM时，ONO - 4057不抑制fMLP或C5a诱导的中性粒细胞活化。在体内研究中，口服给予ONO - 4057可预防豚鼠中LTB4诱导的短暂性中性粒细胞减少或皮内中性粒细胞迁移（产生50%疗效的剂量（ED50） = 25.6mg/kg或5.3mg/kg）。此外，局部给予ONO - 4057可抑制豚鼠耳部佛波醇 - 12 - 肉豆蔻酸 - 13 - 乙酸酯（PMA）诱导的中性粒细胞浸润（有效剂量 = 1 mg/耳）。这些结果表明ONO - 4057是一种选择性口服活性LTB4拮抗剂，可能是治疗各种炎症性疾病的潜在候选药物。
