Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist
Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist
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DOI：
10.1016/s0049-3848(01)00353-x
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发表时间：
2001-10-15
影响因子：
7.5
通讯作者：
Andrade-Gordon, P
中科院分区：
文献类型：
--
作者：
Damiano, BP;Mitchell, JA;Andrade-Gordon, P
RWJ-53308是一种新型的非肽糖蛋白IIb/IIIa （GPIIb/IIIa）拮抗剂，抑制纤维蛋白原与GPIIb/IIIa的结合，IC50为0.4 +/- 0.3 nM。RWJ-53308抑制凝血素诱导的人凝胶过滤血小板（TC50=60 +/- 12 nM）和人富血小板血浆（PRP）中胶原、花生四烯酸、ADP和SFLLRN-NH2的血小板聚集（IC50分别为60 +/- 10、150 +/- 30、70 +/- 4和160 +/- 80 nM）。RWJ-53308在犬和豚鼠PRP中的效价与人PRP相似。RWJ-53308在0.3 mg/ kg静脉注射后可抑制体外胶原和adp诱导的清醒犬血小板聚集长达4小时，在1和3 mg/ kg静脉注射后可抑制4和6小时。口服生物利用度为16 +/- 7%。RWJ-53308在静脉（0.01-0.1 mg/kg）和口服（3 mg/kg）给药后，可减少犬动静脉（AV）分流模型的血栓重量。在豚鼠颈动脉挤压损伤模型中，RWJ-53308在0.7 mg/kg iv时完全抑制血栓诱导的循环血流减少（CFR）。在光激活和氯化铁诱导的豚鼠血栓形成模型中，RWJ-53308分别在0.3和1 mg/kg iv时阻断血栓形成。总之，RWJ-53308是一种有效的口服活性GPIIb/IIIa拮抗剂，可用于动脉血栓性疾病的急性和慢性治疗。2001爱思唯尔科学有限公司版权所有。
RWJ-53308 is a novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist that inhibits fibrinogen binding to GPIIb/IIIa with an IC50 of 0.4 +/- 0.3 nM. RWJ-53308 inhibits thrombin-induced platelet aggregation in human gel-filtered platelets (TC50=60 +/- 12 nM) and platelet aggregation in human platelet-rich plasma (PRP) in response to collagen, arachidonic acid, ADP, and SFLLRN-NH2 (IC50 = 60 +/- 10, 150 +/- 30, 70 +/- 4, and 160 +/- 80 nM, respectively). The potency of RWJ-53308 in dog and guinea pig PRP is similar to human PRP. RWJ-53308 inhibits ex vivo collagen- and ADP-induced platelet aggregation in conscious dogs for up to 4 h following 0.3 mg/ kg iv, and through 4 and 6 h following 1 and 3 mg/ kg po. Oral bioavailability is 16 +/- 7%. RWJ-53308 reduces thrombus weight in a canine arteriovenous (AV) shunt model following intravenous (0.01-0.1 mg/kg) and oral (3 mg/kg) administration. In a guinea pig carotid artery pinch-injury model, RWJ-53308 completely suppresses thrombus-induced cyclic flow reductions (CFR) at 0.7 mg/kg iv. RWJ-53308 also blocks thrombus formation in photoactivation- and ferric chloride-induced models of thrombosis in guinea pigs at 0.3 and 1 mg/kg iv, respectively. In summary, RWJ-53308 is a potent orally active GPIIb/IIIa antagonist that may be useful for both acute and chronic treatment of arterial thrombotic disorders. (C) 2001 Elsevier Science Ltd. All rights reserved.