SK&amp;F 106760, a novel GPIIB/IIIA antagonist: antithrombotic activity and potentiation of streptokinase-mediated thrombolysis

Nichols, Andrew J.; Vasko, J.; Koster, Paul F.; Smith, Jean A.; Barone, Frank C.; Nelson, Allyson G.; Stadel, Jeffrey M.; Powers, David; Rhodes, Glen R.; Miller‐Stein, Cynthia; Boppana, Venkatta; Bennet, D.; Berry, David E.; Romoff, Todd T.; Calvo, Raul R.; Ali, Fadia E.; Sorenson, E.; Samanen, James M.

doi:10.1016/0014-2999(90)92378-v

Cited by 26 publications

(13 citation statements)

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“…The enhanced binding affinity observed with protein GP IIb-IIla antagonists may be attributed to favorabvle conformational restraints of the RGD sequence and/or the presence of secondary binding determinants in the protein. The former hypothesis is supported by the fact that relatively small constrained cyclic RGD-containing peptides can inhibit fibrinogen/GP Ilb-11Ia binding and inhibit platelet aggregation with potencies comparable to those of the natural protein GP IIb-IIIa antagonists [43]. In addition, replacement of the RGD sequence in echistatin [44] or kistrin (unpublished results) with other amino acids leads to significantly less potent proteins,.…”

Section: Sequence Similarity To Other Gp Ilh-liiu Protein Untagonistsmentioning

confidence: 67%

Ornatins: potent glycoprotein IIb‐IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata

Mazur

Henzel²,

Seymour³

et al. 1991

European Journal of Biochemistry

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The purification and characterization of six isoforms of ornatin, potent glycoprotein Ilb-IIIa (GP IIb-IlIa) antagonists and platelet aggregation inhibitors are described. These isoforms were purified from whole leech homogenates of the leech Plucohdella ornata, a North American leech commonly known as the turtle leech, by trichloroacetic acid precipitation, Sephadex G-50 size exclusion chromatography, G P IIb-IIIa affinity chromatography, and CIS reverse-phase HPLC. Each of the five completely sequenced isoforms, which range from 41 to 52 residues in length, contains the Arg-Gly-Asp (RGD) sequence, a common recognition sequence in adhesion proteins, as well as 6 cysteine residues; the positions of both of these features are conserved in the primary sequences. The amino acid sequences of ornatin isoforms B, C, D, and E are highly conserved, whereas ornatin A2 and A3 are less similar and lack 9 residues at the N-terminus. The ornatins are approximately 40% identical with decorsin, a GP IIb-IIIa antagonist isolated from the leech Mncrobddlu decoru

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Section: Sequence Similarity To Other Gp Ilh-liiu Protein Untagonistsmentioning

confidence: 67%

Ornatins: potent glycoprotein IIb‐IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata

Mazur

Henzel²,

Seymour³

et al. 1991

European Journal of Biochemistry

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“…The first of these compounds is SKF-106,760, which is a tetrapeptide cyclized with penicillamine to produce a ring structure (30). This compound displayed potent inhibition of platelet-dependent thrombus formation in stenosed canine coronary arteries (effective dose 1-3 mg/kg, iv) and accelerated streptokinase (SK)-induced thrombolysis from 34±8tol4±3 min.…”

Section: Fibrinogen Receptor Antagonistsmentioning

confidence: 99%

Interruption of Thrombosis and Hemostasis by Anti-Platelet Agents

Shebuski

1993

Toxicol Pathol

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Blood platelets play a fundamental role in hemostasis and thrombosis. The physiological role of platelets is to preserve the integrity of the cardiovascular system such that upon injury platelets are activated and serve to interrupt a potentially deleterious situation (i.e., hemorrhage). However, platelets are also involved in the pathophysiology of thrombosis in which the normal repair process is grossly exacerbated, resulting in interruption of blood flow to vital tissues. Thus, a critical balance exists between the normal function of blood platelets to preserve tissue function and a pathophysiological function in which tissue is damaged due to thrombosis and subsequent ischemia. Numerous anti-platelet agents have been developed in an attempt to interrupt the thrombotic process without severely compromising the hemostatic state of patients. This article will be devoted to a discussion of a commonly utilized anti-thrombotic agent, aspirin, as well as a class of newer, possibly more effective anti-thrombotic agents referred to collectively as fibrinogen receptor antagonists.

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“…22 SK&F 106760 is a novel RGD mimic capable of competitively inhibiting fibrinogen binding to GP lib/ Ilia. 10 In accord with this action, SK&F 106760 inhibits in vitro platelet aggregation elicited by all known endogenous agonists. The demonstrated efficacy of antiplatelet agents (e.g., aspirin and ticlopidine) in the treatment of TIA and prevention of stroke in high-risk patients 67 led us to examine the antiplatelet and antithrombotic effects of SK&F 106760.…”

mentioning

confidence: 95%

“…to platelet plasma membrane GP Ilb/IIIa (fibrinogen receptor) and a potent inhibitor of human platelet aggregation induced by a variety of agonists in vitro. 10 Unlike aspirin, SK&F 106760 is believed to inhibit the final common pathway of platelet aggregation. 10 We evaluated the effects of SK&F 106760 on ex vivo platelet aggregation in dogs.…”

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confidence: 99%

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Antithrombotic effects of a platelet fibrinogen receptor antagonist in a canine model of carotid artery thrombosis.

Willette

Sauermelch

Rycyna

et al. 1992

Stroke

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Background and Purpose: Platelet-fibrin thrombi in the lumen of atherostenotic carotid arteries may underlie transient ischemic attacks and cerebral infarction. For this reason, we investigated the antiplatelet and antithrombotic effects of a novel and potent platelet fibrinogen receptor (glycoprotein Ilb/lIIa) antagonist (SK&F 106760).Methods: The effects of 0.1-3.0 mg/kg i.v. SK&F 106760 on platelet aggregation were examined ex vivo in canine platelet-rich plasma (n=20). In addition, the antithrombotic effects of SK&F 106760 were compared with those of aspirin in an acute canine model of extracranial carotid artery thrombosis with high-grade stenosis. Sham-operated (n=4), vehicle-treated (n=6), SK&F 106760-treated (n=8), aspirintreated (n=9), and SK&F 106760+aspirin-treated (n=5) dogs were examined.Results: The intravenous administration of SK&F 106760 caused a dose-related inhibition of ex vivo platelet aggregation. In the carotid artery thrombosis model, an occlusive thrombus formed at stenotic sites in the region of the carotid bifurcation. The thrombogenic process caused a progressive reduction in carotid blood flow and reduced the cortical microvascular perfusion and electroencephalographic power. Based on nuclear magnetic resonance spectroscopy, the occlusive events depleted the stores of high-energy phosphates (adenosine triphosphate and phosphocreatine) and increased the lactate concentration in the forelimb somatosensory area of the parietal cortex. In this model, the administration of 1 mg/kg i.v. SK&F 106760 prevented thrombosis of the stenotic carotid artery. Consequently, neurophysiological, cerebral hemodynamic, and metabolic parameters were all improved significantly in the SK&F 106760-treated group. No dog receiving SK&F 106760 reoccluded during the 1-hour posttreatment observation period. In contrast, thrombosis of the carotid artery was associated with neurophysiological deterioration in six of the nine dogs treated with S mg/kg i.v. aspirin. Both spontaneous and evoked (increased carotid stenosis) aspirin-resistant thrombosis were abolished by SK&F 106760 treatment Conclusions: These results suggest that antagonism of fibrinogen binding to platelet glycoprotein Ilb/IIIa (the final common pathway for aggregation) may represent a new and more effective antithrombotic approach to the treatment of cerebral transient ischemic attacks and infarction associated with extracranial carotid artery disease. (Stroke 1992^3:703-711)

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SK&F 106760, a novel GPIIB/IIIA antagonist: antithrombotic activity and potentiation of streptokinase-mediated thrombolysis

Cited by 26 publications

References 0 publications

Ornatins: potent glycoprotein IIb‐IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata

Ornatins: potent glycoprotein IIb‐IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata

Interruption of Thrombosis and Hemostasis by Anti-Platelet Agents

Antithrombotic effects of a platelet fibrinogen receptor antagonist in a canine model of carotid artery thrombosis.

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