Nichols A J, Vasko J A, Valocik R E, Kopaciewicz L J, Storer B L, Ali F E, Romoff T, Calvo R, Samanen J M
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Thromb Res. 1994 Jul 15;75(2):143-56. doi: 10.1016/0049-3848(94)90063-9.
The properties of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methyl-arginyl-glycyl-aspartyl-penicillamine-amide] as a GPIIb/IIIa antagonist have been studied in vitro and compared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 530 +/- 73 nM. In canine platelet rich plasma Ac-RGDS-NH2 produced a concentration related inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 microM. However, incubation in platelet rich plasma for 3 hr abolished the activity of Ac-RGDS-NH2. SK&F 106760 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosphate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor receptor (GPIb/IX)-mediated platelet agglutination produced by ristocetin. In canine platelet rich plasma SK&F 106760 inhibited aggregation produced by adenosine diphosphate, collagen and epinephrine/U-46619 with IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respectively and in gel filtered platelets inhibited thrombin-mediated aggregation with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 in platelet rich plasma for three hours had no significant effect on its ability to inhibit adenosine diphosphate-induced platelet aggregation. SK&F 106760 produced insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve to fibrinogen in adenosine diphosphate-activated platelets with a Kb of 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GPIIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).
已在体外研究了SK&F 106760 [Nα-乙酰基-环（S，S）-半胱氨酰-Nα-甲基-精氨酰-甘氨酰-天冬氨酰-青霉胺酰胺]作为糖蛋白IIb/IIIa拮抗剂的特性，并与母体分子Ac-RGDS-NH2进行了比较。Ac-RGDS-NH2抑制生物素化纤维蛋白原与固定在塑料微量滴定板上的纯化人糖蛋白IIb/IIIa的结合，其抑制常数（Ki）为530±73 nM。在犬富含血小板血浆中，预孵育3分钟后，Ac-RGDS-NH2对二磷酸腺苷诱导的血小板聚集产生浓度依赖性抑制，半数抑制浓度（IC50）为91±1 μM。然而，在富含血小板血浆中孵育3小时后，Ac-RGDS-NH2的活性消失。SK&F 106760抑制生物素化纤维蛋白原与固定在塑料微量滴定板上的纯化人糖蛋白IIb/IIIa的结合，其Ki为477±57 pM。SK&F 106760抑制人富含血小板血浆中二磷酸腺苷诱导的血小板聚集，IC50为230±60 nM，但不抑制瑞斯托霉素诱导的血管性血友病因子受体（糖蛋白Ib/IX）介导的血小板凝集。在犬富含血小板血浆中，SK&F 106760抑制二磷酸腺苷、胶原和肾上腺素/U-46619诱导的聚集，IC50值分别为355±35、260±20和490±90 nM，在凝胶过滤血小板中抑制凝血酶介导的聚集，IC50为188±10 nM。SK&F 106760在富含血小板血浆中预孵育3小时对其抑制二磷酸腺苷诱导的血小板聚集的能力没有显著影响。在纤维蛋白原浓度恒定的情况下，SK&F 106760对二磷酸腺苷诱导的血小板聚集产生不可克服的抑制作用，但在二磷酸腺苷激活的血小板中对纤维蛋白原浓度-反应曲线产生竞争性抑制作用，平衡解离常数（Kb）为8.0±1.0 nM。因此，SK&F 106760是一种强效、稳定的竞争性糖蛋白IIb/IIIa拮抗剂，在血管性血友病因子受体（糖蛋白Ib/IX）上未检测到活性。
