Mousa S A, Bozarth J M, Naik U P, Slee A
DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA.
Br J Pharmacol. 2001 Jun;133(3):331-6. doi: 10.1038/sj.bjp.0703943.
A number of non-peptide orally active RGD mimetic prodrug such as Orbofiban, Sibrafiban, SR121566, Roxifiban and others entered into the clinical evaluation stage. Some of these agents were terminated and some are still in clinical trials. The present study examined the platelet GPIIb/IIIa binding profiles for the active form of Roxifiban, Sibrafiban, SR121566 and Orbofiban using 3H-Roxifiban active form (XV459), 3H-DMP728, 125I-Echistatin, and 125I-Fibrinogen. Either DMP728, Orbofiban, Sibrafiban, SR121566 or Roxifiban active form as well as other RGD mimetic bind to the same binding site(s) on human platelets as evident from the competitive inhibition of binding of each other to human platelet. Additionally, Roxifiban active form competed with FITC labeled GPIIb/IIIa antagonist cyclic RGD peptidomimetic (XL086) as demonstrated using confocal microscopy technique. Roxifiban active form (XV459) demonstrated the highest potency in inhibiting 3H-XV459, 3H-DMP728, 125I-Echistatin, and 125I-Fibrinogen binding to human platelets as compared to the others. Structure activity relationship within the isoxazoline Roxifiban series showed that substituent at the alpha-carbon next to the carboxy terminal represents an exosite for the affinity binding to human platelets leading to slow platelet dissociation rate. These data indicated a distinct binding profile for Roxifiban (high affinity to both activated and resting platelets associated with a relatively slow K(off)) as compared to others. These differences might determine the pharmacodynamics and pharmackokinetics of the different GPIIb/IIIa antagonists.
一些非肽类口服活性RGD模拟前药，如奥波非班、西拉非班、SR121566、罗昔非班等进入了临床评价阶段。其中一些药物已终止试验，一些仍在临床试验中。本研究使用3H-罗昔非班活性形式（XV459）、3H-DMP728、125I-echistatin和125I-纤维蛋白原，检测了罗昔非班、西拉非班、SR121566和奥波非班活性形式与血小板糖蛋白IIb/IIIa的结合情况。从DMP728、奥波非班、西拉非班、SR121566或罗昔非班活性形式以及其他RGD模拟物相互竞争结合人血小板的情况可以明显看出，它们都与人血小板上的相同结合位点结合。此外，使用共聚焦显微镜技术证明，罗昔非班活性形式与异硫氰酸荧光素标记的糖蛋白IIb/IIIa拮抗剂环RGD肽模拟物（XL086）存在竞争。与其他药物相比，罗昔非班活性形式（XV459）在抑制3H-XV459、3H-DMP728、125I-echistatin和125I-纤维蛋白原与人血小板结合方面表现出最高的效力。异恶唑啉罗昔非班系列的构效关系表明，羧基末端旁边α-碳上的取代基是与人血小板亲和力结合的一个外位点，导致血小板解离速率缓慢。这些数据表明，与其他药物相比，罗昔非班具有独特的结合特征（对活化和静息血小板均具有高亲和力，且解离常数相对较慢）。这些差异可能决定了不同糖蛋白IIb/IIIa拮抗剂的药效学和药代动力学。
