Fretland D J, Anglin C P, Bremer M, Isakson P, Widomski D L, Paulson S K, Docter S H, Djuric S W, Penning T D, Yu S
Department of Inflammatory Diseases Research, Searle Research and Development, Chesterfield, Missouri, USA.
Inflammation. 1995 Apr;19(2):193-205. doi: 10.1007/BF01534461.
Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.
白三烯B4（LTB4）和12（R）-羟基二十碳四烯酸[12（R）-HETE]是花生四烯酸代谢的促炎产物，在多种炎症性疾病中被认为是介质。当皮内注射到豚鼠体内时，LTB4和12（R）-HETE会引起中性粒细胞（PMN）向注射部位的剂量依赖性迁移（趋化作用），这可通过中性粒细胞标记酶髓过氧化物酶的存在来评估。第一代LTB4受体拮抗剂SC-41930（7-[3-（4-乙酰基-3-甲氧基-2-丙基苯氧基）丙氧基]-3,4-二氢-8-丙基-2H-1-苯并吡喃-2-羧酸）口服时以1.7mg/kg的半数有效剂量（ED50）抑制LTB4的趋化作用。第二代LTB4受体拮抗剂SC-53228[（+）-（S）-7-（3-（2-（环丙基甲基）-3-甲氧基-4-[(甲氨基)羰基]苯氧基）丙氧基]-3,4-二氢-8-丙基-2H-1-苯并吡喃-2-丙酸]胃内给药时以0.07mg/kg的ED50值抑制LTB4诱导的趋化作用。此外，SC-53228以5.8mg/kg的口服ED50值抑制12（R）-HETE诱导的粒细胞趋化作用。当以0.03-100mg/kg的范围口服给药时，SC-53228的血浆峰浓度（Cmax）为0.015-41.1微克/毫升。SC-53228以34nM的半数抑制浓度（IC50）抑制LTB4引发的人中性粒细胞膜去极化。作为一种有效的LTB4受体拮抗剂，SC-53228很可能在哮喘、类风湿性关节炎、炎症性肠病、接触性皮炎和银屑病等疾病状态的医学治疗中具有应用价值，在这些疾病中LTB4和/或12（R）-HETE被认为是炎症介质。
