GPIIB/IIIA antagonists

GPIIb/IIIa antagonists have to be administered parenterally. They are currently used prophylactically during intracoronary interventions such as percutaneous transluminal revascularization with balloon angioplasty or intracoronary stenting, as well as to treat acute coronary syndromes like unstable angina and acute myocardial infarction. The main complications... 

Constrained templates for fibrinogen receptor (GPIIb/IIIa) antagonists 2001BML2619... 

Tenecteplase (TNKase) [Thrombolytic/Recombinant Tissue Plasminogen Activator] Uses Restore perfusion i mortality w/ AMI Action Thrombolytic TPA Dose 30-50 mg see Table III-l Caution [C, ], T Bleeding w/ NSAIDs, ticlopidine, clopidogrel, GPIIb/IIIa antagonists Contra Bleeding, CVA, major surgery (intracranial, intraspinal) or trauma w/in... 

Scheme 41 p-Tum Peptidomimetics as Platelet Glycoprotein gpIIb/IIIa Antagonists 1581... 

Scheme 42 Preparation of p-Tum Peptidomimetics as gpIIb/IIIa Antagonists Based on the Nipecotic Acid Template11581...

TEG in Phase II clinical trial in monitoring the efficacy of oral platelet GPIIb/IIIa antagonist on platelet/fibrin clot dynamics. 

Fig. 2. Three-dimensional computer-generated representation of platelet adhesion and subsequent aggregation on collagen I/von Willebrand factor from normal heparinized blood perfused in the absence (control) or presence of a GPIIb/IIIa antagonist (XV454) at 37 °C for 1 min at 1500 sec-1...

In this assay, immobilized platelets are pretreated with a GPIIb/IIIa antagonist, and any unbound drug is washed away before the perfusion of monocytic THP-1 cells. McCarty et al. (2004) demonstrated that agents with slow platelet off-rates such as XV454 (ti/2 of dissociation = 110 min Kd = 1 nM) and abciximab (ti/2 of dissociation = 40 min Kd = 9.0 nM) that are distributed predominantly as receptor-bound entities with little unbound in the plasma, can effectively block these heterotypic interactions as shown by Abulencia et al. (2001) and by Mousa et al. (2002). In contrast, agents with relatively fast platelet dissociation rates such as orbofiban (ti/2 of dissociation = 0.2 min Kd > 110 nM), whose antiplatelet efficacy depend on the plasma concentration of the active drug, do not exhibit any inhibitory effects as described by Mousa etal. (2002). 

Abulencia JP, Tien N, McCarty OJT et al. (2001) Comparative antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist (XV454) and Abciximab (c7E3) in flow models of thrombosis. Arterioscler Thromb Vase Biol 21 149-156 McCarty OJ, Abulencia JP, Mousa SA, Konstantopoulos K (2004) Evaluation of platelet antagonists in in vitro flow models of thrombosis. Methods Mol Med 93 21-34... 

Mousa SA, DeGrado WF, Mu D-X et al. (1996) Oral antiplatelet antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa antagonist. Circulation 93 537-543... 

Cox D, Motoyama Y, Seki J et al. (1992) Pentamadine a nonpeptide GPIIb/IIIa antagonist - in vitro studies on platelets from humans and other species. Thromb Haemostasis 68 731-736... 

Nichols. A.J. et al. (1992) Development of GPIIb/IIIa antagonists as antithrombotic drugs. Trends Pharmacol. Sci., 13, 413-417. 

P. N. Zannikos, S. Rohatagi, B. K. Jensen, S. L. DePhillips, and G. R. Rhodes, Pharmacokinetics and concentration-effect analysis of intravenous RGD891, a platelet GPIIb/IIIa antagonist, using mixed-effects modeling (NONMEM). J Clin Pharmacol 40 1129-1140 (2000). 

Takada, S., T. Kurokawa, K. Miyazaki, S. Iwasa, and Y. Ogawa. 1997. Utilization of an amorphous form of a water-soluble GPIIb/IIIa antagonist for controlled release from biodegradable microspheres. Pharm. Res. 14 (9) 1146—1150. 

Glycoprotein GPIIb/IIIa antagonists currently available for intravenous use as antithrombotics following coronary angioplasty (PTCA) represent a recently introduced class of drugs and contain one of the few monoclonal antibodies used as therapeutic, abciximab. 

Cox D (2004) Oral GPIIb/IIIa antagonists what went wrong Curr Pharm Des 10 1587-1596... 

Nurden, A.T., Nurden, P. GPIIb/IIIa antagonists and other anti-integrins. Semin. Vascular Med. 2003, 3, 123-130. 

Coller B S (1997). Platelet GPIIb/IIIa antagonists the first anti-integrin receptor therapeutics./. Clin. Investigat. 100(suppl 11) S57-S60. 

In the course of research into orally active GPIIb/IIIa antagonists, the syntheses and biological activities of masked amidines as prodrugs were evaluated. In the synthetic studies, a 5-cyano-oxadiazole derivative was prepared from its corresponding carbaldoxime by dehydration with TFAA/pyridine [1082]. 

Harada, T, Katada, J., Tachiki, A., Asari, T, lijima, K., Uno, I., Ojima, I. and Hayashi, Y, Development of the new potent non-peptide GpIIb/IIIa antagonist NSL-95301 by utilizing combinatorial technique, Bioorg. Med. Chem. Lett., 7 (1997) 209-212. 

Hoel996 Hoekstra, W.J., Maryanoff, B.E., Andrade-Gordon, R, Cohen, J.H., Costanzo, M.J., Damiano, B.P., Haertlein, B.J., Harris, B.D., Kauffman, J.A., Keane, P.M., McComsey, D.F., Villani, F.J. and Yabut, S.C., Solid-Phase Parallel Synthesis Applied to Lead Optimization Discovery of Potent Analogs of GPIIb/IIIa Antagonist RWJ-50042, Bioorg. Med. Chem. Lett., 6 (1996) 2371-2376. 

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