Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist

被引:28
作者
Damiano, BP [1 ]
Mitchell, JA [1 ]
Giardino, E [1 ]
Corcoran, T [1 ]
Haertlein, BJ [1 ]
de Garavilla, L [1 ]
Kauffman, JA [1 ]
Hoekstra, WJ [1 ]
Maryanoff, BE [1 ]
Andrade-Gordon, P [1 ]
机构
[1] RW Johnson Pharmaceut Res Inst, Drug Discovery, Spring House, PA 19477 USA
关键词
glycoprotein IIb/IIIa; GPIIb/IIIa receptor antagonist; platelet aggregation; thrombosis; antithrombotic;
D O I
10.1016/S0049-3848(01)00353-X
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:113 / 126
页数:14
相关论文
共 49 条
[1]   COLLABORATIVE OVERVIEW OF RANDOMIZED TRIALS OF ANTIPLATELET THERAPY .1. PREVENTION OF DEATH, MYOCARDIAL-INFARCTION, AND STROKE BY PROLONGED ANTIPLATELET THERAPY IN VARIOUS CATEGORIES OF PATIENTS [J].
ALTMAN, R ;
CARRERAS, L ;
DIAZ, R ;
FIGUEROA, E ;
PAOLASSO, E ;
PARODI, JC ;
CADE, JF ;
DONNAN, G ;
EADIE, MJ ;
GAVAGHAN, TP ;
OSULLIVAN, EF ;
PARKIN, D ;
RENNY, JTG ;
SILAGY, C ;
VINAZZER, H ;
ZEKERT, F ;
ADRIAENSEN, H ;
BERTRANDHARDY, JM ;
BRAN, M ;
DAVID, JL ;
DRICOT, J ;
LAVENNEPARDONGE, E ;
LIMET, R ;
LOWENTHAL, A ;
MORIAU, M ;
SCHAPIRA, S ;
SMETS, P ;
SYMOENS, J ;
VERHAEGHE, R ;
VERSTRAETE, M ;
ATALLAH, A ;
BARNETT, H ;
BATISTA, R ;
BLAKELY, J ;
CAIRNS, JA ;
COTE, R ;
CROUCH, J ;
EVANS, G ;
FINDLAY, JM ;
GENT, M ;
LANGLOIS, Y ;
LECLERC, J ;
NORRIS, J ;
PINEO, GF ;
POWERS, PJ ;
ROBERTS, R ;
SCHWARTZ, L ;
SICURELLA, J ;
TAYLOR, W ;
THEROUX, P .
BMJ-BRITISH MEDICAL JOURNAL, 1994, 308 (6921) :81-100
[2]   Comparison of the antithrombotic effects of FK633, GPIIb/IIIa antagonist, and aspirin in a guinea pig thrombosis model [J].
Aoki, T ;
Cox, D ;
Senzaki, K ;
Seki, J ;
Tanaka, A ;
Takasugi, H ;
Motoyama, Y .
THROMBOSIS RESEARCH, 1998, 89 (03) :129-136
[3]  
Bazzino O, 1998, NEW ENGL J MED, V338, P1488
[4]   USE OF A MONOCLONAL-ANTIBODY DIRECTED AGAINST THE PLATELET GLYCOPROTEIN IIB/IIIA RECEPTOR IN HIGH-RISK CORONARY ANGIOPLASTY [J].
CALIFF, RM ;
SHADOFF, N ;
VALETT, N ;
BATES, E ;
GALEANA, A ;
KNOPF, W ;
SHAFTEL, J ;
BENDER, MJ ;
AVERSANO, T ;
RAQUENO, J ;
GURBEL, P ;
COWFER, J ;
COHEN, M ;
CROSS, P ;
BITTL, J ;
EDDINGS, K ;
TAYLOR, M ;
DEROSA, K ;
HATTEL, L ;
COOPER, L ;
ESHELMAN, B ;
FINTEL, D ;
NIEMYSKI, P ;
KLEIN, L ;
KENNEDY, H ;
THORNTON, T ;
KEREIAKES, D ;
MARTIN, L ;
ANDERSON, L ;
HIGBY, N ;
ELLIS, S ;
BREZINA, K ;
GEORGE, B ;
CHAPEKIS, A ;
SMITH, D ;
ANWAR, A ;
GERBER, TL ;
PRITCHARD, GL ;
MYLER, R ;
SHAW, R ;
MURPHY, M ;
WARD, K ;
MADIGAN, NP ;
BLANKENSHIP, J ;
HALBERT, M ;
FLANAGAN, C ;
TANNENBAUM, M ;
POLICH, M ;
STEVENSON, C ;
TCHENG, J .
NEW ENGLAND JOURNAL OF MEDICINE, 1994, 330 (14) :956-961
[5]  
Cannon CP, 1998, CIRCULATION, V97, P340
[6]   Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial [J].
Cannon, CP ;
McCabe, CH ;
Wilcox, RG ;
Langer, A ;
Caspi, A ;
Berink, P ;
Lopez-Sendon, J ;
Toman, J ;
Charlesworth, A ;
Anders, RJ ;
Alexander, JC ;
Skene, A ;
Braunwald, E .
CIRCULATION, 2000, 102 (02) :149-156
[7]  
CARROLL RC, 1999, CURR OPIN CARDIOVASC, V1, P131
[8]  
Chew DP, 2001, CIRCULATION, V103, P201
[9]   A critical appraisal of platelet glycoprotein IIb/IIIa inhibition [J].
Chew, DP ;
Moliterno, DJ .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2000, 36 (07) :2028-2035
[10]  
Coller BS, 1997, J CLIN INVEST, V100, pS57