Herbert J M, Bernat A, Valette G, Gigo V, Lale A, LaPlace M C, Lespy L, Savi P, Maffrand J P, Le Fur G
Sanofi Recherche, Toulouse, France.
J Pharmacol Exp Ther. 1991 Oct;259(1):44-51.
SR 27417 [N-(2-dimethylamino ethyl)-N-(3-pyridinyl methyl)[4- (2,4,6-triisopropylphenyl) thiazol-2-yl]amine] is the first member of a newly developed platelet-activating factor (PAF) antagonist series. It is a highly potent, competitive and selective antagonist of the binding of [3H]PAF to its receptor in rabbit platelets. It exhibits an equilibrium inhibition constant for PAF binding of 57 pM, a value that is at least 5-fold lower than that of unlabeled PAF itself. SR 27417 potently inhibited PAF-induced aggregation of rabbit and human platelets in vitro (IC50 = 0.10 and 0.50 nM, respectively) but had no effect on the action of other platelet-aggregating agents. In comparison with the triazolothienodiazepine WEB-2086, SR 27417 was 470 and 70 times more potent against PAF-induced aggregation of rabbit and human platelets, respectively. SR 27417 displayed marked in vitro inhibition of PAF-induced oxidative burst in guinea pig macrophages (IC50 = 32 nM). In an in vivo model, it protected mice from 100 micrograms/kg PAF-induced death when given i.v. (ED50 = 7.5 micrograms/kg) 5 min before PAF challenge or p.o. (ED50 = 45 micrograms/kg) 3 hr before PAF administration. SR 27417 inhibited PAF-induced death in mice with an impressive p.o. or i.v. duration of action of 30 to 48 hr. In anesthetized guinea pigs, SR 27417 inhibited i.v. and p.o. 100 ng/kg PAF-induced bronchoconstriction (ED50 = 14 and 140 micrograms/kg, respectively), hemoconcentration (ED50 = 20 and 270 micrograms/kg, respectively), thrombocytopenia (ED50 = 30 and 240 micrograms/kg, respectively) and leukopenia (ED50 = 0.1 and 1.5 mg/kg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
SR 27417 [N-（2-二甲基氨基乙基）-N-（3-吡啶基甲基）[4-（2,4,6-三异丙基苯基）噻唑-2-基]胺]是新开发的血小板活化因子（PAF）拮抗剂系列的首个成员。它是一种高效、竞争性且选择性的[3H]PAF与兔血小板中其受体结合的拮抗剂。它对PAF结合的平衡抑制常数为57 pM，该值比未标记的PAF本身至少低5倍。SR 27417在体外能有效抑制PAF诱导的兔和人血小板聚集（IC50分别为0.10和0.50 nM），但对其他血小板聚集剂的作用无影响。与三唑并噻吩二氮杂䓬WEB-2086相比，SR 27417对PAF诱导的兔和人血小板聚集的效力分别高470倍和70倍。SR 27417在体外对PAF诱导的豚鼠巨噬细胞氧化爆发有显著抑制作用（IC50 = 32 nM）。在体内模型中，在PAF攻击前5分钟静脉注射（ED50 = 7.5微克/千克）或在PAF给药前3小时口服（ED50 = 45微克/千克）时，它能保护小鼠免受100微克/千克PAF诱导的死亡。SR 27417抑制小鼠PAF诱导的死亡，口服或静脉注射的作用持续时间令人印象深刻，为30至48小时。在麻醉的豚鼠中，SR 27417抑制静脉注射和口服100 ng/千克PAF诱导的支气管收缩（ED50分别为14和140微克/千克）、血液浓缩（ED50分别为20和270微克/千克）、血小板减少（ED50分别为30和240微克/千克）和白细胞减少（ED50分别为0.1和1.5毫克/千克）。（摘要截断于250字）
