Kanayama T, Kimura Y, Iseki K, Hayashi Y, Tamao Y, Mizogami S
Pharmaceuticals Laboratory, Mitsubishi Kasei Corporation, Yokohama, Japan.
J Pharmacol Exp Ther. 1990 Dec;255(3):1210-7.
A chemically stable prostacyclin analog, KP-10614 [(4z,16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9;alpha)-9(o)- methano-PGI1], has been compared with two other prostacyclin derivatives (Iloprost and TEI-7165) and one prostaglandin E1 derivative (OP-1206) with respect to ADP-induced in vitro aggregation of human platelets and ex vivo platelet aggregation in rats and dogs, given by bolus injection and i.v. infusion. These compounds were also tested on the systemic arterial blood pressure of rats and dogs. KP-10614 was the most potent inhibitor of in vitro platelet aggregation induced by ADP with IC50 of 1 nM among the compounds studied in this report, and it also showed ex vivo effectiveness at doses much lower than the other three compounds. KP-10614 was also orally active. At oral doses of 25, 50 and 100 micrograms/kg, this new compound caused a dose-dependent inhibition of ex vivo platelet aggregation in rats, whereas the other three compounds were effective only at 500 micrograms/kg or more. In addition, KP-10614 showed definite antithrombotic effects at a dose range of 0.1 to 1 microgram/kg i.v. in various thrombosis models in which platelet aggregation was mainly involved. These results indicate that KP-10614 possesses therapeutic potential in thrombotic diseases.
一种化学性质稳定的前列环素类似物KP-10614 [(4z,16s)-4,5,18,18,19,19-六脱氢-16,20-二甲基-δ6(9;α)-9(o)-亚甲基-PGI1],已与另外两种前列环素衍生物(伊洛前列素和TEI-7165)以及一种前列腺素E1衍生物(OP-1206),就静脉推注和静脉输注给药后对人血小板ADP诱导的体外聚集以及大鼠和犬的体内血小板聚集进行了比较。这些化合物还在大鼠和犬的体循环动脉血压上进行了测试。在本报告研究的化合物中,KP-10614是ADP诱导的体外血小板聚集的最有效抑制剂,IC50为1 nM,并且在比其他三种化合物低得多的剂量下也显示出体内有效性。KP-10614口服也有活性。在25、50和100微克/千克的口服剂量下,这种新化合物对大鼠体内血小板聚集产生剂量依赖性抑制,而其他三种化合物仅在500微克/千克或更高剂量时才有效。此外,在主要涉及血小板聚集的各种血栓形成模型中,KP-10614在0.1至1微克/千克的静脉注射剂量范围内显示出明确的抗血栓作用。这些结果表明,KP-10614在血栓性疾病中具有治疗潜力。