L-663,536 (MK-886) (3-[1-(4-CHLOROBENZYL)-3-T-BUTYL-THIO-5-ISOPROPYLINDOL-2-YL]-2,2-DIMETHYLPROPANOIC ACID), A NOVEL, ORALLY ACTIVE LEUKOTRIENE BIOSYNTHESIS INHIBITOR
L-663,536 (MK-886) (3-[1-(4-CHLOROBENZYL)-3-T-BUTYL-THIO-5-ISOPROPYLINDOL-2-YL]-2,2-DIMETHYLPROPANOIC ACID), A NOVEL, ORALLY ACTIVE LEUKOTRIENE BIOSYNTHESIS INHIBITOR
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DOI：
10.1139/y89-073
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发表时间：
1989-05-01
影响因子：
2.1
通讯作者：
PACHOLOK, S
中科院分区：
文献类型：
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作者：
GILLARD, J;FORDHUTCHINSON, AW;PACHOLOK, S
L-663,536(3-[1-(4-chorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2，2-dimethylpropanoic酸)是一种有效的白三烯(LT)生物合成的抑制剂。同样，L-663,536可抑制A23187诱导的大鼠外周血LTB_4的形成，并能诱导中性粒细胞的产生。在人全血中出现白三烯生物合成抑制的浓度(1.1µm)，对环氧合酶或12-脂氧合酶没有影响，在洗涤的人血小板中也观察到这种影响。该化合物对大鼠和猪的5-脂氧合酶无影响，提示L-663,536不是直接的5-脂氧合酶抑制剂。体内给药时，L-663,536对甲基丝氨酸(ED50，0.036 mg/kg P.O.)处理的近交系大鼠的抗原性呼吸困难有明显的抑制作用。对小鼠蛔虫致小鼠支气管收缩作用(1 mg/kg，P.O.)。该化合物在大鼠胸膜炎模型(ED50，0.2 mg/kg P.O.)、炎症大鼠足爪模型(ED50，0.8 mg/kg)、抗原激发后大鼠胆汁中白三烯排泄模型以及豚鼠耳局部注射离子载体A23187(ED50，2.5 mg/kg P.O.)诱导白三烯合成的模型中，抑制了白三烯的体内生物合成。和0.6µg外用)。结果表明，L-663,536在体外和体内都是白三烯生物合成的有效抑制剂，表明该化合物适合于研究白三烯在各种病理情况下的作用。
L-663,536 (3-[1-(4-chorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact huan polymorphonuclear leukocytes (PMN) (IC50, 2.5 nM). Similarly, L-663,536 inhibited A23187-induced LTB4 formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1 .mu.M), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 .mu.g topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.