Ushiyama S, Ito T, Asai F, Oshima T, Terada A, Matsuda K, Yamazaki M
New Lead Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Thromb Res. 1988 Sep 1;51(5):507-20. doi: 10.1016/0049-3848(88)90116-8.
RS-5186, sodium 6-[2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene]- carboxylate, inhibited platelet thromboxane A2 (TXA2) synthetase with IC50 values of 6 nM and 13 nM for human and rabbit microsomes, respectively. It had a selectivity for TXA2 synthetase 10(5)-fold greater than that for cyclooxygenase, PGI2 synthetase, 5-lipoxygenase and phospholipase A2. When administered orally or intravenously to dogs at 1 mg/kg, RS-5186 suppressed serum TXB2 levels almost completely with sustained duration of action: the suppression during 0.5 hr to 8 hr after dosing was more than 90%, and was 70-80% at 24 hr. Similar suppression of serum TXB2 levels was observed in rats and rabbits. Such suppression by RS-5186 was more potent than that by OKY-046 and CV-4151. Serial administration of RS-5186 (0.1 mg/kg/day p.o.) to dogs for 7 days decreased the serum TXB2 levels constantly during the medication, and no rebound phenomenon was observed after the medication was stopped. In a thrombotic model induced by sodium arachidonate injection in rabbits, RS-5186 at 1 mg/kg p.o. completely protected against sudden death (ED50 = 0.12 mg/kg, 1 hr after dosing) and this protective effect extended over 8 hr. All these results show that RS-5186 is a potent and highly selective TXA2 synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in diseases where TXA2 is involved.
RS - 5186，即6 - [2 - [1 - (1H) - 咪唑基]甲基 - 4,5 - 二氢苯并[b]噻吩] - 羧酸钠，对人及兔微粒体中的血小板血栓素A2（TXA2）合成酶具有抑制作用，其IC50值分别为6 nM和13 nM。它对TXA2合成酶的选择性比对环氧化酶、前列环素（PGI2）合成酶、5 - 脂氧合酶和磷脂酶A2高10⁵倍。当以1 mg/kg的剂量口服或静脉注射给犬时，RS - 5186几乎完全抑制血清TXB2水平，且作用持续时间持久：给药后0.5小时至8小时的抑制率超过90%，24小时时为70 - 80%。在大鼠和兔中也观察到了类似的血清TXB2水平抑制情况。RS - 5186的这种抑制作用比OKY - 046和CV - 4151更强。对犬连续7天口服RS - 5186（0.1 mg/kg/天）可使血清TXB2水平在用药期间持续下降，停药后未观察到反弹现象。在兔用花生四烯酸钠注射诱导的血栓形成模型中，口服1 mg/kg的RS - 5186可完全预防猝死（ED50 = 0.12 mg/kg，给药后1小时），且这种保护作用可持续8小时。所有这些结果表明，RS - 5186是一种强效且高度选择性的TXA2合成酶抑制剂，作用持续时间长，提示该化合物可能对涉及TXA2的疾病有用。
