Mousa S A, Forsythe M, Lorelli W, Bozarth J, Xue C B, Wityak J, Sielecki T M, Olson R E, DeGrado W, Kapil R, Hussain M, Wexler R, Thoolen M J, Reilly T M
DuPont Merck Pharmaceutical Co., Wilmington, Delaware, USA.
Coron Artery Dis. 1996 Oct;7(10):767-74. doi: 10.1097/00019501-199610000-00010.
To define the antiplatelet efficacy and specificity of the glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist prodrug DMP754 and its free acid form, XV459.
DMP754 has an IC50 > 1 mumol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting human platelet aggregation induced by 10 mumol/l adenosine diphosphate, 20 micrograms/ml collagen, 1 mmol/l epinephrine, 10 mumol/l platelet activating factor or 0.5 IU/ml thrombin. The in-vitro rate of hydrolysis of DMP754 or XV459 is much faster with human or canine liver esterases (t 1/2 = 2.4-23 min) than with plasma esterases (t 1/2 = 5.5-7.6 h). Platelet GpIIb/IIIa integrin binding affinity and specificity for XV459 were determined using cell binding/adhesion assays.
The range of IC50 values of XV459 in inhibiting platelet aggregation in platelet-rich plasma obtained from 12 subjects was 0.035-0.069 mumol/l with a mean IC50 of 0.050 +/- 0.003 mumol/l. Additionally, XV459 inhibited platelets obtained from mongrel dogs, baboons, sheep, guinea pigs, and mice with IC50 in the range 0.024-0.06 mumol/l, and IC50 in the range 0.16-5.8 mumol/l in pigs, rabbits, and rats. XV459 inhibited [125I]-fibrinogen binding to activated human platelets with an IC50 of 0.011 +/- 0.003 mumol/l. XV459 demonstrated a high degree of selectivity in specifically inhibiting fibrinogen binding to the platelet integrin, GPIIb/IIIa (IC50 = 0.00025 +/- 0.00005 mumol/l) compared with inhibiting other integrins (alpha v beta 3, IC50 > 10 mumol/l; or alpha v beta 5, alpha 5 beta 1, or alpha 4 beta 1, for which the IC50 exceeded 100 mumol/l).
DMP754 is a potent antiplatelet agent in inhibiting platelet aggregation, and has a high specificity and affinity for human platelet GPIIb/IIIa receptors.
确定糖蛋白IIb/IIIa复合物（GPIIb/IIIa）拮抗剂前体药物DMP754及其游离酸形式XV459的抗血小板疗效和特异性。
DMP754的IC50>1μmol/l，在经酯酶转化为游离酸形式后，在抑制由10μmol/l二磷酸腺苷、20μg/ml胶原、1mmol/l肾上腺素、10μmol/l血小板活化因子或0.5IU/ml凝血酶诱导的人血小板聚集方面显示出高效力（IC50为20 - 45nmol/l）。DMP754或XV459在体外被人或犬肝酯酶水解的速率（t1/2 = 2.4 - 23分钟）比被血浆酯酶水解的速率（t1/2 = 5.5 - 7.6小时）快得多。使用细胞结合/黏附试验测定血小板GpIIb/IIIa整合素对XV459的结合亲和力和特异性。
XV459在抑制从12名受试者获得的富血小板血浆中血小板聚集时的IC50值范围为0.035 - 0.069μmol/l，平均IC50为0.050±0.003μmol/l。此外，XV459抑制杂种犬、狒狒、绵羊、豚鼠和小鼠的血小板，IC50在0.024 - 0.06μmol/l范围内，而在猪、兔和大鼠中IC50在0.16 - 5.8μmol/l范围内。XV459抑制[125I] - 纤维蛋白原与活化的人血小板结合，IC50为0.011±0.003μmol/l。与抑制其他整合素（αvβ3，IC50>10μmol/l；或αvβ5、α5β1或α4β1，其IC50超过100μmol/l）相比，XV459在特异性抑制纤维蛋白原与血小板整合素GPIIb/IIIa结合方面表现出高度选择性（IC50 = 0.00025±0.00005μmol/l）。
DMP754是一种强效抗血小板剂，在抑制血小板聚集方面具有高特异性和对人血小板GPIIb/IIIa受体的高亲和力。
